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Shahar Gabay T, Stolero N, Rabhun N, Sabah R, Raz O, Neumeier Y, Marx Z, Tao L, Biezuner T, Amir S, Adar R, Levy R, Chapal-Ilani N, Evtiugina N, Shlush LI, Shapiro E, Yehudai-Resheff S, Zuckerman T. GMP-like and MLP-like Subpopulations of Hematopoietic Stem and Progenitor Cells Harboring Mutated EZH2 and TP53 at Diagnosis Promote Acute Myeloid Leukemia Relapse: Data of Combined Molecular, Functional, and Genomic Single-Stem-Cell Analyses. Int J Mol Sci 2025; 26:4224. [PMID: 40362463 PMCID: PMC12072498 DOI: 10.3390/ijms26094224] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2025] [Revised: 04/20/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
Acute myeloid leukemia (AML) is associated with unfavorable patient outcomes primarily related to disease relapse. Since specific types of leukemic hematopoietic stem and progenitor cells (HSPCs) are suggested to contribute to AML propagation, this study aimed to identify and explore relapse-initiating HSPC subpopulations present at diagnosis, using single-cell analysis (SCA). We developed unique high-resolution techniques capable of tracking single-HSPC-derived subclones during AML evolution. Each subclone was evaluated for chemo-resistance, in vivo leukemogenic potential, mutational profile, and the cell of origin. In BM samples of 15 AML patients, GMP-like and MLP-like HSPC subpopulations were identified as prevalent at relapse, exhibiting chemo-resistance to commonly used chemotherapy agents cytosine arabinoside (Ara-C) and daunorubicin. Reconstruction of phylogenetic lineage trees combined with genetic analysis of single HSPCs and single-HSPC-derived subclones demonstrated two distinct clusters, originating from MLP-like or GMP-like subpopulations, observed both at diagnosis and relapse. These subpopulations induced leukemia development ex vivo and in vivo. Genetic SCA showed that these relapse-related subpopulations harbored mutated EZH2 and TP53, detected already at diagnosis. This study, using combined molecular, functional, and genomic analyses at the level of single cells, identified patient-specific chemo-resistant HSPC subpopulations at the time of diagnosis, promoting AML relapse.
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MESH Headings
- Leukemia, Myeloid, Acute/genetics
- Leukemia, Myeloid, Acute/pathology
- Leukemia, Myeloid, Acute/diagnosis
- Leukemia, Myeloid, Acute/metabolism
- Leukemia, Myeloid, Acute/drug therapy
- Humans
- Enhancer of Zeste Homolog 2 Protein/genetics
- Single-Cell Analysis/methods
- Hematopoietic Stem Cells/metabolism
- Hematopoietic Stem Cells/pathology
- Tumor Suppressor Protein p53/genetics
- Mutation
- Animals
- Male
- Female
- Middle Aged
- Mice
- Recurrence
- Adult
- Cytarabine/pharmacology
- Drug Resistance, Neoplasm/genetics
- Aged
- Neoplastic Stem Cells/metabolism
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Affiliation(s)
- Tal Shahar Gabay
- Hematology Research Center, Clinical Research Institute at Rambam, Rambam Health Care Campus, Haifa 3109601, Israel; (T.S.G.); (R.S.); (S.Y.-R.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa 3109601, Israel
| | - Nofar Stolero
- Hematology Research Center, Clinical Research Institute at Rambam, Rambam Health Care Campus, Haifa 3109601, Israel; (T.S.G.); (R.S.); (S.Y.-R.)
| | - Niv Rabhun
- Hematology Research Center, Clinical Research Institute at Rambam, Rambam Health Care Campus, Haifa 3109601, Israel; (T.S.G.); (R.S.); (S.Y.-R.)
| | - Rawan Sabah
- Hematology Research Center, Clinical Research Institute at Rambam, Rambam Health Care Campus, Haifa 3109601, Israel; (T.S.G.); (R.S.); (S.Y.-R.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa 3109601, Israel
| | - Ofir Raz
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 761001, Israel; (O.R.); (Y.N.); (L.T.); (R.L.); (E.S.)
| | - Yaara Neumeier
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 761001, Israel; (O.R.); (Y.N.); (L.T.); (R.L.); (E.S.)
- Department of Immunology, Weizmann Institute of Science, Rehovot 761001, Israel; (T.B.); (N.C.-I.); (L.I.S.)
| | - Zipora Marx
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 761001, Israel; (O.R.); (Y.N.); (L.T.); (R.L.); (E.S.)
| | - Liming Tao
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 761001, Israel; (O.R.); (Y.N.); (L.T.); (R.L.); (E.S.)
| | - Tamir Biezuner
- Department of Immunology, Weizmann Institute of Science, Rehovot 761001, Israel; (T.B.); (N.C.-I.); (L.I.S.)
| | - Shiran Amir
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 761001, Israel; (O.R.); (Y.N.); (L.T.); (R.L.); (E.S.)
| | - Rivka Adar
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 761001, Israel; (O.R.); (Y.N.); (L.T.); (R.L.); (E.S.)
| | - Ron Levy
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 761001, Israel; (O.R.); (Y.N.); (L.T.); (R.L.); (E.S.)
| | - Noa Chapal-Ilani
- Department of Immunology, Weizmann Institute of Science, Rehovot 761001, Israel; (T.B.); (N.C.-I.); (L.I.S.)
| | - Natalia Evtiugina
- Hematology Research Center, Clinical Research Institute at Rambam, Rambam Health Care Campus, Haifa 3109601, Israel; (T.S.G.); (R.S.); (S.Y.-R.)
| | - Liran I. Shlush
- Department of Immunology, Weizmann Institute of Science, Rehovot 761001, Israel; (T.B.); (N.C.-I.); (L.I.S.)
| | - Ehud Shapiro
- Department of Computer Science and Applied Mathematics, Weizmann Institute of Science, Rehovot 761001, Israel; (O.R.); (Y.N.); (L.T.); (R.L.); (E.S.)
| | - Shlomit Yehudai-Resheff
- Hematology Research Center, Clinical Research Institute at Rambam, Rambam Health Care Campus, Haifa 3109601, Israel; (T.S.G.); (R.S.); (S.Y.-R.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa 3109601, Israel
| | - Tsila Zuckerman
- Hematology Research Center, Clinical Research Institute at Rambam, Rambam Health Care Campus, Haifa 3109601, Israel; (T.S.G.); (R.S.); (S.Y.-R.)
- The Ruth and Bruce Rappaport Faculty of Medicine, Technion, Haifa 3109601, Israel
- Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa 3109601, Israel
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Mohammed MH, Al-Aouadi RFA, Uthirapathy S, Sanghvi G, M M R, Abdulamer RS, Prasad GVS, Kundlas M, Khamraev F, Ullah MI. Therapeutic innovations: targeting ROS production in AML with natural and synthetic compounds. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-04054-6. [PMID: 40163149 DOI: 10.1007/s00210-025-04054-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/05/2025] [Accepted: 03/12/2025] [Indexed: 04/02/2025]
Abstract
Reactive oxygen species (ROS) play a dual role in the pathophysiology of acute myeloid leukemia (AML), functioning as both signaling molecules and agents of cellular damage. This review offers an in-depth analysis of ROS production in AML, highlighting their impact on essential cellular pathways that govern cell survival, proliferation, and apoptosis. It explores both natural and synthetic pharmacological agents that modulate ROS generation and enhance oxidative stress, assessing their therapeutic potential and the challenges they present in clinical practice. Additionally, the review identifies ROS-associated prognostic biomarkers that could enhance patient stratification and improve treatment outcomes in AML. Despite the promising potential of ROS-targeted therapies, significant challenges remain, such as the complexity of ROS dynamics, resistance mechanisms, and the influence of the tumor microenvironment. This review aims to shed light on current advancements and emphasize the need for further research to refine therapeutic strategies that leverage the ROS pathway in AML.
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Affiliation(s)
- Mohammed Hashim Mohammed
- Medical Laboratory Techniques Department, College of Health and Medical Technology, Al-Maarif University, Anbar, Iraq.
| | | | - Subasini Uthirapathy
- Pharmacy Department, Tishk International University, Erbil, Kurdistan Region, Iraq
| | - Gaurav Sanghvi
- Department of Microbiology, Faculty of Science, Marwadi University Research Center, Marwadi University, Rajkot, 360003, Gujarat, India
| | - Rekha M M
- Department of Chemistry and Biochemistry, School of Sciences, JAIN (Deemed to Be University), Bangalore, Karnataka, India
| | - Resan Shakir Abdulamer
- Department of Medical Laboratories Technology, Al-Nisour University College, Nisour Seq. Karkh, Baghdad, Iraq
| | - G V Siva Prasad
- Department of Chemistry, Raghu Engineering College, Visakhapatnam, Andhra Pradesh, 531162, India
| | - Mayank Kundlas
- Centre for Research Impact & Outcome, Chitkara University Institute of Engineering and Technology, Chitkara University, Rajpura, 140401, Punjab, India
| | | | - Muhammad Ikram Ullah
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Jouf University, 72388, Sakaka, Aljouf, Saudi Arabia
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Zhou J, Sui P, Zhao J, Cheng X, Yu T, Cui S, Song X, Xing C. Benzene-induced hematotoxicity enhances the self-renewal ability of HSPCs in Mll-Af9 mice. Toxicology 2025; 511:154061. [PMID: 39842622 DOI: 10.1016/j.tox.2025.154061] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2024] [Revised: 12/11/2024] [Accepted: 01/17/2025] [Indexed: 01/24/2025]
Abstract
Patients with benzene-induced leukemia undergo a continuous transformation from myelosuppression to malignant proliferation. However, the underlying mechanisms in this process remain unknown. Our previous studies have shown that the pathways involved in self-renewal capacity of bone marrow (BM) cells in Mll-Af9 mice exposed to benzene for life are significantly activated after severe blood toxicity. In order to investigate the hematotoxicity effects of benzene on the self-renewal capacity of HSCs, Mll-Af9 chimeric mice were exposed to benzene and hematological parameters were dynamically monitored after benzene exposure. Transcriptomic analysis were used to analyze different time points during benzene exposure and after competitive bone marrow transplantation (BMT). Results showed that despite severe hematotoxicity in mice, but the chimerism rate of Mll-Af9 cells in peripheral blood (PB) cells was significantly increased after 10 weeks benzene exposure (P < 0.001). After competitive BMT, the chimerism rate of Mll-Af9 cells from 10 weeks benzene-exposed mice was gradually increased and significantly surpassed that of the control at 26 weeks of bone marrow reconstruction (benzene group 86 % VS control group 78 %, P = 0.03). Transcriptome analysis revealed that the expression levels of self-renewal related genes, such as Hox genes (Hoxb4, Hoxa7, Hoxa10), Mecom and Ms4a in BM cells of 10 weeks benzene-exposed mice were relatively higher compared to those in the control group, but no significant difference were observed. Interestingly, Hoxa7, Hoxa10 and Mecom were significantly up-regulated at 26 weeks after bone marrow transplantation. In conclusion, our study suggests that abnormal expression of self-renewal-related genes may be potential early biomarkers for benzene-induced hematotoxicity. This hematotoxicity may contribute to the acquisition of evolutionary advantages by leukemic precursor cells and accelerate malignant transformation.
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Affiliation(s)
- Jin Zhou
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China; China State Key Laboratory of Trauma, Burn and Combined Injury, China
| | - Pinpin Sui
- CAS Key Laboratory of Genomic and Precision Medicine, Collaborative Innovation Center of Genetics and Development, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China; China National Center for Bioinformation, Beijing, China; University of Chinese Academy of Sciences, Beijing, China
| | - Jianxin Zhao
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China; National Office for Maternal and Child Health Surveillance of China, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Xiurong Cheng
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China; China State Key Laboratory of Trauma, Burn and Combined Injury, China
| | - Tao Yu
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China; China State Key Laboratory of Trauma, Burn and Combined Injury, China
| | - Shiwei Cui
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China; China State Key Laboratory of Trauma, Burn and Combined Injury, China
| | - Xiangrong Song
- Institute of Toxicology, Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou, China
| | - Caihong Xing
- Key Laboratory of Chemical Safety and Health, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China; China State Key Laboratory of Trauma, Burn and Combined Injury, China.
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Ebinama U, George B. Revolutionizing acute myeloid leukemia treatment: a systematic review of immune-based therapies. Discov Oncol 2025; 16:89. [PMID: 39864030 PMCID: PMC11769894 DOI: 10.1007/s12672-025-01797-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 01/10/2025] [Indexed: 01/27/2025] Open
Abstract
The established protocol for the management of acute myeloid leukemia (AML) has traditionally involved the administration of induction chemotherapy, followed by consolidation chemotherapy, and subsequent allogeneic stem cell transplantation for eligible patients. However, the prognosis for individuals with relapsed and refractory AML remains unfavorable. In response to the necessity for more efficacious therapeutic modalities, targeted immunotherapy has emerged as a promising advancement in AML treatment. This comprehensive review article specifically examines classical unconjugated and toxin-conjugated monoclonal antibodies, which are currently in the preclinical phase or undergoing evaluation in clinical trials. The review delves into the proposed mechanisms through which these monoclonal antibodies elicit anti-tumor activity and identifies the challenges associated with designing targeted immunotherapy. The review focuses on targeting specific antigens in AML, including FLT3/CD125, CLL-1, CD33, CD38, CD47, CD70, and CD123.
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Affiliation(s)
- Ugochi Ebinama
- Department of Internal Medicine, The University of Texas Health Sciences Center at Houston, McGovern Medical School, Houston, TX, USA
| | - Binsah George
- Division of Hematology/Oncology, The University of Texas Health Sciences Center at Houston, McGovern Medical School, 6431 Fannin Street, MSB 5.216, Houston, TX, 77030, USA.
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Mattioda C, Voena C, Ciardelli G, Mattu C. In Vitro 3D Models of Haematological Malignancies: Current Trends and the Road Ahead? Cells 2025; 14:38. [PMID: 39791739 PMCID: PMC11720277 DOI: 10.3390/cells14010038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2024] [Revised: 12/23/2024] [Accepted: 12/30/2024] [Indexed: 01/12/2025] Open
Abstract
Haematological malignancies comprise a diverse group of life-threatening systemic diseases, including leukaemia, lymphoma, and multiple myeloma. Currently available therapies, including chemotherapy, immunotherapy, and CAR-T cells, are often associated with important side effects and with the development of drug resistance and, consequently, disease relapse. In the last decades, it was largely demonstrated that the tumor microenvironment significantly affects cancer cell proliferation and tumor response to treatment. The development of biomimetic, in vitro models may promote the investigation of the interactions between cancer cells and the tumor microenvironment and may help to better understand the mechanisms leading to drug resistance. Although advanced in vitro models have been largely explored in the field of solid tumors, due to the complex nature of the blood cancer tumor microenvironment, the mimicking of haematological malignancies mostly relies on simpler systems, often limited to two-dimensional cell culture, which intrinsically excludes the microenvironmental niche, or to ethically debated animal models. This review aims at reporting an updated overview of state-of-the-art hematological malignancies 3D in vitro models, emphasizing the key features and limitations of existing systems to inspire further research in this underexplored field.
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Affiliation(s)
- Carlotta Mattioda
- DIMEAS, Politecnico di Torino, C.so Duca degli Abruzzi 24, 10129 Torino, Italy; (C.M.); (G.C.)
| | - Claudia Voena
- Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Torino, 10126 Torino, Italy;
| | - Gianluca Ciardelli
- DIMEAS, Politecnico di Torino, C.so Duca degli Abruzzi 24, 10129 Torino, Italy; (C.M.); (G.C.)
| | - Clara Mattu
- DIMEAS, Politecnico di Torino, C.so Duca degli Abruzzi 24, 10129 Torino, Italy; (C.M.); (G.C.)
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He G, Jiang L, Zhou X, Gu Y, Tang J, Zhang Q, Hu Q, Huang G, Zhuang Z, Gao X, Xu K, Xiao Y. Single-cell transcriptomics reveals heterogeneity and prognostic markers of myeloid precursor cells in acute myeloid leukemia. Front Immunol 2024; 15:1494106. [PMID: 39737198 PMCID: PMC11683592 DOI: 10.3389/fimmu.2024.1494106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Accepted: 10/29/2024] [Indexed: 01/01/2025] Open
Abstract
Background Acute myeloid leukemia (AML) is a hematologic tumor with poor prognosis and significant clinical heterogeneity. By integrating transcriptomic data, single-cell RNA sequencing data and independently collected RNA sequencing data this study aims to identify key genes in AML and establish a prognostic assessment model to improve the accuracy of prognostic prediction. Materials and methods We analyzed RNA-seq data from AML patients and combined it with single-cell RNA sequencing data to identify genes associated with AML prognosis. Key genes were screened by bioinformatics methods, and a prognostic assessment model was established based on these genes to validate their accuracy. Results The study identified eight key genes significantly associated with AML prognosis: SPATS2L, SPINK2, AREG, CLEC11A, HGF, IRF8, ARHGAP5, and CD34. The prognostic model constructed on the basis of these genes effectively differentiated between high-risk and low-risk patients and revealed differences in immune function and metabolic pathways of AML cells. Conclusion This study provides a new approach to AML prognostic assessment and reveals the role of key genes in AML. These genes may become new biomarkers and therapeutic targets that can help improve prognostic prediction and personalized treatment of AML.
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Affiliation(s)
- Guangfeng He
- Department of Hematology, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lai Jiang
- Department of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Xuancheng Zhou
- Department of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Yuheng Gu
- Department of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Jingyi Tang
- Department of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Qiang Zhang
- Department of Laboratory Medicine, Southwest Medical University, Luzhou, China
| | - Qingwen Hu
- Department of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Gang Huang
- Department of Clinical Medicine, Southwest Medical University, Luzhou, China
| | - Ziye Zhuang
- First Clinical Medical College, Guangdong Medical University, Zhanjiang, China
| | - Xinrui Gao
- Department of Oncology, Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Ke Xu
- Department of Oncology, Chongqing General Hospital, Chongqing University, Chongqing, China
| | - Yewei Xiao
- Department of Physiology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
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Chen X, Yuan Y, Zhou F, Li L, Pu J, Jiang X. RNA modification in normal hematopoiesis and hematologic malignancies. MedComm (Beijing) 2024; 5:e787. [PMID: 39445003 PMCID: PMC11496571 DOI: 10.1002/mco2.787] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2024] [Revised: 09/26/2024] [Accepted: 09/26/2024] [Indexed: 10/25/2024] Open
Abstract
N6-methyladenosine (m6A) is the most abundant RNA modification in eukaryotic cells. Previous studies have shown that m6A plays a critical role under both normal physiological and pathological conditions. Hematopoiesis and differentiation are highly regulated processes, and recent studies on m6A mRNA methylation have revealed how this modification controls cell fate in both normal and malignant hematopoietic states. However, despite these insights, a comprehensive understanding of its complex roles between normal hematopoietic development and malignant hematopoietic diseases remains elusive. This review first provides an overview of the components and biological functions of m6A modification regulators. Additionally, it highlights the origin, differentiation process, biological characteristics, and regulatory mechanisms of hematopoietic stem cells, as well as the features, immune properties, and self-renewal pathways of leukemia stem cells. Last, the article systematically reviews the latest research advancements on the roles and mechanisms of m6A regulatory factors in normal hematopoiesis and related malignant diseases. More importantly, this review explores how targeting m6A regulators and various signaling pathways could effectively intervene in the development of leukemia, providing new insights and potential therapeutic targets. Targeting m6A modification may hold promise for achieving more precise and effective leukemia treatments.
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Affiliation(s)
- Xi Chen
- Department of NeurosurgeryThe Second Affiliated Hospital of Kunming Medical UniversityKunmingChina
- NHC Key Laboratory of Drug Addiction MedicineKunming Medical UniversityKunmingYunnanChina
| | - Yixiao Yuan
- Department of MedicineUF Health Cancer CenterUniversity of FloridaGainesvilleFloridaUSA
- Department of Medicine and Department of Biochemistry and Molecular BiologyUniversity of FloridaGainesvilleFloridaUSA
| | - Fan Zhou
- Department of NeurosurgeryThe Second Affiliated Hospital of Kunming Medical UniversityKunmingChina
- NHC Key Laboratory of Drug Addiction MedicineKunming Medical UniversityKunmingYunnanChina
| | - Lihua Li
- NHC Key Laboratory of Drug Addiction MedicineKunming Medical UniversityKunmingYunnanChina
| | - Jun Pu
- Department of NeurosurgeryThe Second Affiliated Hospital of Kunming Medical UniversityKunmingChina
- NHC Key Laboratory of Drug Addiction MedicineKunming Medical UniversityKunmingYunnanChina
| | - Xiulin Jiang
- Department of MedicineUF Health Cancer CenterUniversity of FloridaGainesvilleFloridaUSA
- Department of Medicine and Department of Biochemistry and Molecular BiologyUniversity of FloridaGainesvilleFloridaUSA
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Sheridan M, Maqbool MA, Largeot A, Clayfield L, Xu J, Moncaut N, Sellers R, Whittle J, Paggetti J, Iqbal M, Aucagne R, Delva L, Baker SM, Lie-A-Ling M, Kouskoff V, Lacaud G. The small inhibitor WM-1119 effectively targets KAT6A-rearranged AML, but not KMT2A-rearranged AML, despite shared KAT6 genetic dependency. J Hematol Oncol 2024; 17:91. [PMID: 39380002 PMCID: PMC11462755 DOI: 10.1186/s13045-024-01610-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2024] [Accepted: 09/20/2024] [Indexed: 10/10/2024] Open
Abstract
BACKGROUND The epigenetic factors KAT6A (MOZ/MYST3) and KMT2A (MLL/MLL1) interact in normal hematopoiesis to regulate progenitors' self-renewal. Both proteins are recurrently translocated in AML, leading to impairment of critical differentiation pathways in these malignant cells. We evaluated the potential of different KAT6A therapeutic targeting strategies to alter the growth of KAT6A and KMT2A rearranged AMLs. METHODS We investigated the action and potential mechanisms of the first-in-class KAT6A inhibitor, WM-1119 in KAT6A and KMT2A rearranged (KAT6Ar and KMT2Ar) AML using cellular (flow cytometry, colony assays, cell growth) and molecular (shRNA knock-down, CRISPR knock-out, bulk and single-cell RNA-seq, ChIP-seq) assays. We also used two novel genetic murine KAT6A models combined with the most common KMT2Ar AML, KMT2A::MLLT3 AML. In these murine models, the catalytic activity of KAT6A, or the whole protein, can be conditionally abrogated or deleted. These models allowed us to compare the effects of specific KAT6A KAT activity inhibition with the complete deletion of the whole protein. Finally, we also tested these therapeutic approaches on human AML cell lines and primary patient AMLs. RESULTS We found that WM-1119 completely abrogated the proliferative and clonogenic potential of KAT6Ar cells in vitro. WM-1119 treatment was associated with a dramatic increase in myeloid differentiation program. The treatment also decreased stemness and leukemia pathways at the transcriptome level and led to loss of binding of the fusion protein at critical regulators of these pathways. In contrast, our pharmacologic and genetic results indicate that the catalytic activity of KAT6A plays a more limited role in KMT2Ar leukemogenicity, while targeting the whole KAT6A protein dramatically affects leukemic potential in murine KMT2A::MLLT3 AML. CONCLUSION Our study indicates that inhibiting KAT6A KAT activity holds compelling promise for KAT6Ar AML patients. In contrast, targeted degradation of KAT6A, and not just its catalytic activity, may represent a more appropriate therapeutic approach for KMT2Ar AMLs.
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Affiliation(s)
- Mathew Sheridan
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Muhammad Ahmad Maqbool
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
- GSK Medicines Research Centre, Stevenage, UK
| | - Anne Largeot
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
- Department of Cancer Research, Tumor Stroma Interactions, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Liam Clayfield
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Jingru Xu
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Natalia Moncaut
- Genome Editing and Mouse Models, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Robert Sellers
- Computational Biology Support, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Jessica Whittle
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Jerome Paggetti
- Department of Cancer Research, Tumor Stroma Interactions, Luxembourg Institute of Health, Luxembourg, Luxembourg
| | - Mudassar Iqbal
- Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Romain Aucagne
- UFR des Sciences de Santé, Inserm U1231, Université de Bourgogne, Team Epi2THM, LipSTIC Labex, Dijon, France
| | - Laurent Delva
- UFR des Sciences de Santé, Inserm U1231, Université de Bourgogne, Team Epi2THM, LipSTIC Labex, Dijon, France
| | - Syed Murtuza Baker
- Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK
| | - Michael Lie-A-Ling
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK
| | - Valerie Kouskoff
- Division of Developmental Biology and Medicine, The University of Manchester, Manchester, UK
| | - Georges Lacaud
- Stem Cell Biology Group, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, UK.
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Lints R, Walker CA, Delfi O, Prouse M, PohLui De Silva M, Bohlander SK, Wood AC. Mutational cooperativity of RUNX1::RUNX1T1 isoform 9a and oncogenic NRAS in zebrafish myeloid leukaemia. Biol Open 2024; 13:bio060523. [PMID: 39177514 PMCID: PMC11381922 DOI: 10.1242/bio.060523] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Accepted: 08/01/2024] [Indexed: 08/24/2024] Open
Abstract
RUNX1::RUNX1T1 (R::RT1) acute myeloid leukaemia (AML) remains a clinical challenge, and further research is required to model and understand leukaemogenesis. Previous zebrafish R::RT1 models were hampered by embryonic lethality and low penetrance of the malignant phenotype. Here, we overcome this by developing an adult zebrafish model in which the human R::RT1 isoform 9a is co-expressed with the frequently co-occurring oncogenic NRASG12D mutation in haematopoietic stem and progenitor cells (HSPCs), using the Runx1+23 enhancer. Approximately 50% of F0 9a+NRASG12D transgenic zebrafish developed signs of haematological disease between 5 and 14 months, with 27% exhibiting AML-like pathology: myeloid precursor expansion, erythrocyte reduction, kidney marrow hypercellularity and the presence of blasts. Moreover, only 9a+NRASG12D transplant recipients developed leukaemia with high rates of mortality within 40 days, inferring the presence of leukaemia stem cells. These leukaemic features were rare or not observed in animals expressing either the NRAS or 9a oncogenes alone, suggesting 9a and NRAS cooperation drives leukaemogenesis. This novel adult AML zebrafish model provides a powerful new tool for investigating the basis of R::RT1 - NRAS cooperativity with the potential to uncover new therapeutic targets.
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Affiliation(s)
- Robyn Lints
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1023, New Zealand
| | - Christina A. Walker
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1023, New Zealand
| | - Omid Delfi
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1023, New Zealand
| | - Matthew Prouse
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1023, New Zealand
| | | | - Stefan K. Bohlander
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1023, New Zealand
| | - Andrew C. Wood
- Leukaemia and Blood Cancer Research Unit, Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1023, New Zealand
- Starship Child Health, Starship Blood and Cancer Centre, Auckland 1023, New Zealand
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10
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Wen X, Li P, Ma Y, Wang D, Jia R, Xia Y, Li W, Li Y, Li G, Sun T, Lu F, Ye J, Ji C. RHOF activation of AKT/β-catenin signaling pathway drives acute myeloid leukemia progression and chemotherapy resistance. iScience 2024; 27:110221. [PMID: 39021805 PMCID: PMC11253531 DOI: 10.1016/j.isci.2024.110221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/29/2024] [Accepted: 06/05/2024] [Indexed: 07/20/2024] Open
Abstract
Acute myeloid leukemia (AML) is a clonal malignancy originating from leukemia stem cells, characterized by a poor prognosis, underscoring the necessity for novel therapeutic targets and treatment methodologies. This study focuses on Ras homolog family member F, filopodia associated (RHOF), a Rho guanosine triphosphatase (GTPase) family member. We found that RHOF is overexpressed in AML, correlating with an adverse prognosis. Our gain- and loss-of-function experiments revealed that RHOF overexpression enhances proliferation and impedes apoptosis in AML cells in vitro. Conversely, genetic suppression of RHOF markedly reduced the leukemia burden in a human AML xenograft mouse model. Furthermore, we investigated the synergistic effect of RHOF downregulation and chemotherapy, demonstrating significant therapeutic efficacy in vivo. Mechanistically, RHOF activates the AKT/β-catenin signaling pathway, thereby accelerating the progression of AML. Our findings elucidate the pivotal role of RHOF in AML pathogenesis and propose RHOF inhibition as a promising therapeutic approach for AML management.
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Affiliation(s)
- Xin Wen
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Peng Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Yuechan Ma
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Dongmei Wang
- Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China
| | - Ruinan Jia
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Yuan Xia
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Wei Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Yongjian Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Guosheng Li
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
- Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China
| | - Tao Sun
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
- Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China
| | - Fei Lu
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
| | - Jingjing Ye
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
- Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China
| | - Chunyan Ji
- Department of Hematology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan 250012, People’s Republic of China
- Shandong Key Laboratory of Immunohematology, Qilu Hospital, Shandong University, Jinan 250012, People’s Republic of China
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11
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Aalam SMM, Nguyen LV, Ritting ML, Kannan N. Clonal tracking in cancer and metastasis. Cancer Metastasis Rev 2024; 43:639-656. [PMID: 37910295 PMCID: PMC11500829 DOI: 10.1007/s10555-023-10149-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 10/16/2023] [Indexed: 11/03/2023]
Abstract
The eradication of many cancers has proven challenging due to the presence of functionally and genetically heterogeneous clones maintained by rare cancer stem cells (CSCs), which contribute to disease progression, treatment refractoriness, and late relapse. The characterization of functional CSC activity has necessitated the development of modern clonal tracking strategies. This review describes viral-based and CRISPR-Cas9-based cellular barcoding, lineage tracing, and imaging-based approaches. DNA-based cellular barcoding technology is emerging as a powerful and robust strategy that has been widely applied to in vitro and in vivo model systems, including patient-derived xenograft models. This review also highlights the potential of these methods for use in the clinical and drug discovery contexts and discusses the important insights gained from such approaches.
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Affiliation(s)
| | - Long Viet Nguyen
- Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
| | - Megan L Ritting
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA
| | - Nagarajan Kannan
- Department of Laboratory Medicine and Pathology, Mayo Clinic, 200 First St SW, Rochester, MN, 55905, USA.
- Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA.
- Center for Regenerative Biotherapeutics, Mayo Clinic, Rochester, MN, USA.
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12
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Xu C, Chang W, Jiang H, Liu X, Liu S, Wang D, Xiao Y. Calycosin Induces Ferroptosis by SLC7A11 Through the PI3K/Akt Pathway in Acute Myelocytic Leukemia. REVISTA BRASILEIRA DE FARMACOGNOSIA 2024; 34:776-784. [DOI: 10.1007/s43450-023-00502-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2023] [Accepted: 11/23/2023] [Indexed: 01/03/2025]
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13
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Khorashad JS, Rizzo S, Tonks A. Reactive oxygen species and its role in pathogenesis and resistance to therapy in acute myeloid leukemia. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2024; 7:5. [PMID: 38434766 PMCID: PMC10905166 DOI: 10.20517/cdr.2023.125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/20/2023] [Revised: 01/24/2024] [Accepted: 02/19/2024] [Indexed: 03/05/2024]
Abstract
Relapse following a short clinical response to therapy is the major challenge for the management of acute myeloid leukemia (AML) patients. Leukemic stem cells (LSC), as the source of relapse, have been investigated for their metabolic preferences and their alterations at the time of relapse. As LSC rely on oxidative phosphorylation (OXPHOS) for energy requirement, reactive oxygen species (ROS), as by-products of OXPHOS, have been investigated for their role in the effectiveness of the standard AML therapy. Increased levels of non-mitochondrial ROS, generated by nicotinamide adenine dinucleotide phosphate oxidase, in a subgroup of AML patients add to the complexity of studying ROS. Although there are various studies presenting the contribution of ROS to AML pathogenesis, resistance, and its inhibition or activation as a target, a model that can clearly explain its role in AML has not been conceptualized. This is due to the heterogeneity of AML, the dynamics of ROS production, which is influenced by factors such as the type of treatment, cell differentiation state, mitochondrial activity, and also the heterogeneous generation of non-mitochondrial ROS and limited available data on their interaction with the microenvironment. This review summarizes these challenges and the recent progress in this field.
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Affiliation(s)
- Jamshid Sorouri Khorashad
- Department of Immunology and inflammation, Imperial College London, London, W12 0NN, UK
- Department of Molecular Pathology, Institute of Cancer Research, Sutton, SM2 5PT, UK
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Sian Rizzo
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
| | - Alex Tonks
- Department of Haematology, Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, CF14 4XN, UK
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14
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Heuts BMH, Martens JHA. Understanding blood development and leukemia using sequencing-based technologies and human cell systems. Front Mol Biosci 2023; 10:1266697. [PMID: 37886034 PMCID: PMC10598665 DOI: 10.3389/fmolb.2023.1266697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 09/06/2023] [Indexed: 10/28/2023] Open
Abstract
Our current understanding of human hematopoiesis has undergone significant transformation throughout the years, challenging conventional views. The evolution of high-throughput technologies has enabled the accumulation of diverse data types, offering new avenues for investigating key regulatory processes in blood cell production and disease. In this review, we will explore the opportunities presented by these advancements for unraveling the molecular mechanisms underlying normal and abnormal hematopoiesis. Specifically, we will focus on the importance of enhancer-associated regulatory networks and highlight the crucial role of enhancer-derived transcription regulation. Additionally, we will discuss the unprecedented power of single-cell methods and the progression in using in vitro human blood differentiation system, in particular induced pluripotent stem cell models, in dissecting hematopoietic processes. Furthermore, we will explore the potential of ever more nuanced patient profiling to allow precision medicine approaches. Ultimately, we advocate for a multiparameter, regulatory network-based approach for providing a more holistic understanding of normal hematopoiesis and blood disorders.
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Affiliation(s)
- Branco M H Heuts
- Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, Netherlands
| | - Joost H A Martens
- Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, Netherlands
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15
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Xu J, Sun Y, Fu W, Fu S. MYCT1 in cancer development: Gene structure, regulation, and biological implications for diagnosis and treatment. Biomed Pharmacother 2023; 165:115208. [PMID: 37499454 DOI: 10.1016/j.biopha.2023.115208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 07/10/2023] [Accepted: 07/19/2023] [Indexed: 07/29/2023] Open
Abstract
Myc target 1 (MYCT1), located at 6q25.2, is a crucial player in cancer development. While widely distributed in cells, its subcellular localization varies across different cancer types. As a novel c-Myc target gene, MYCT1 is subject to regulation by multiple transcription factors. Studies have revealed aberrant expression of MYCT1 in various cancers, impacting pivotal biological processes such as proliferation, apoptosis, migration, genomic instability, and differentiation in cancer cells. Additionally, MYCT1 plays a critical role in modulating tumor angiogenesis and remodeling tumor immune responses within the tumor microenvironment. Despite certain debated functions, MYCT1 undeniably holds significance in cancer development. In this review, we comprehensively examine the relationship between MYCT1 and cancer, encompassing gene structure, regulation of gene expression, gene mutation, and biological function, with the aim of providing valuable insights for cancer diagnosis and treatment.
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Affiliation(s)
- Jianan Xu
- Department of Medical genetics, China Medical University, Shenyang 110022, PR China
| | - Yuanyuan Sun
- Department of Medical genetics, China Medical University, Shenyang 110022, PR China
| | - Weineng Fu
- Department of Medical genetics, China Medical University, Shenyang 110022, PR China
| | - Shuang Fu
- Department of Hematology Laboratory, Shengjing Hospital of China Medical University, Shenyang 110022, PR China; Department of Medical genetics, China Medical University, Shenyang 110022, PR China.
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16
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Morii E. Tumor heterogeneity from the viewpoint of pathologists. Pathol Int 2023; 73:394-405. [PMID: 37638598 DOI: 10.1111/pin.13366] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Accepted: 07/30/2023] [Indexed: 08/29/2023]
Abstract
Morphological and functional heterogeneity are found in tumors, with the latter reflecting the different levels of resistance against antitumor therapies. In a therapy-resistant subpopulation, the expression levels of differentiation markers decrease, and those of immature markers increase. In addition, this subpopulation expresses genes involved in drug metabolism, such as aldehyde dehydrogenase 1A1 (ALDH1A1). Because of their similarity to stem cells, cells in the latter therapy-resistant subpopulation are called cancer stem cells (CSCs). Like normal stem cells, CSCs were originally thought not to arise from non-CSCs, but this hierarchical model is too simple. It is now believed that CSCs are generated from non-CSCs. The plasticity of tumor phenotypes between CSCs and non-CSCs causes difficulty in completely curing tumors. In this review, focusing on ALDH1A1 as a marker for CSCs or immature tumor cells, the dynamics of ALDH1A1-expressing tumor cells and their regulatory mechanisms are described, and the plausible regulatory mechanisms of plasticity of ALDH1A1 expression phenotype are discussed. Genetic mutations are a significant factor for tumorigenesis, but non-mutational epigenetic reprogramming factors yielding tumor heterogeneity are also crucial in determining tumor characteristics. Factors influencing non-mutational epigenetic reprogramming in tumors are also discussed.
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Affiliation(s)
- Eiichi Morii
- Department of Pathology, Osaka University Graduate School of Medicine, Osaka, Japan
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17
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Yuan Y, Tan S, Wang H, Zhu J, Li J, Zhang P, Wang M, Zhang F. Mesenchymal Stem Cell-Derived Exosomal miRNA-222-3p Increases Th1/Th2 Ratio and Promotes Apoptosis of Acute Myeloid Leukemia Cells. Anal Cell Pathol (Amst) 2023; 2023:4024887. [PMID: 37621743 PMCID: PMC10447000 DOI: 10.1155/2023/4024887] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/19/2022] [Accepted: 01/25/2023] [Indexed: 08/26/2023] Open
Abstract
Interferon regulatory factor 2 (IRF2) participates in the differentiation of immune T cells. Bone marrow mesenchymal stem cell (BM-MSC)-derived exosomes can secret mRNA, miRNAs, and proteins to regulate tumor microenvironment. The present study focused on the miRNA/IRF2 axis in regulating Th1/Th2 ratio and cell apoptosis in acute myeloid leukemia (AML). The flow cytometry analysis was performed to examine the Th1/Th2 ratio and AML apoptosis in vivo and in vitro. The contents of Interferon γ (IFN-γ) and Interleukin-4 (IL-4) were measured using enzyme-linked immunosorbent assay. StarBase was used to predict the potential binding site between miR-222-3p and the 3' untranslated region of IRF2. Luciferase reporter assay was applied for validating the combination of miR-222-3p and IRF2. BM-MSC exosomes were successfully isolated. BM-MSC exosomes increased Th1/Th2 ratio and promoted apoptosis of AML cells. Further analysis showed that IRF2 was targeted by miR-222-3p. Overexpression of miR-222-3p promoted Th1/Th2 ratio and AML cell apoptosis. IRF2 partially reversed the effect that is exerted by miR-222-3p on Th1/Th2 ratio and AML cell apoptosis. Overexpression of miR-222-3p promoted Th1/Th2 ratio and caspase 3 expression in vivo. To sum up, miR-222-3p promotes Th1/Th2 ratio and AML cell apoptosis by regulating IRF2 expression, which provided crucial targets for the treatment of AML.
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Affiliation(s)
- Yuan Yuan
- Department of Hematology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China
| | - Shengfen Tan
- Department of Hematology, Bengbu Medical College, Bengbu, Anhui 233004, China
| | - Huanhuan Wang
- Department of Hematology, Bengbu Medical College, Bengbu, Anhui 233004, China
| | - Junfeng Zhu
- Department of Hematology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China
| | - Jiajia Li
- Department of Hematology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China
| | - Pingping Zhang
- Department of Hematology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China
| | - Meng Wang
- Department of Hematology, Bengbu Medical College, Bengbu, Anhui 233004, China
| | - Feng Zhang
- Department of Hematology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China
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18
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Barbosa K, Deshpande AJ. Therapeutic targeting of leukemia stem cells in acute myeloid leukemia. Front Oncol 2023; 13:1204895. [PMID: 37601659 PMCID: PMC10437214 DOI: 10.3389/fonc.2023.1204895] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023] Open
Abstract
One of the distinguishing properties of hematopoietic stem cells is their ability to self-renew. Since self-renewal is important for the continuous replenishment of the hematopoietic stem cell pool, this property is often hijacked in blood cancers. Acute myeloid leukemia (AML) is believed to be arranged in a hierarchy, with self-renewing leukemia stem cells (LSCs) giving rise to the bulk tumor. Some of the earliest characterizations of LSCs were made in seminal studies that assessed the ability of prospectively isolated candidate AML stem cells to repopulate the entire heterogeneity of the tumor in mice. Further studies indicated that LSCs may be responsible for chemotherapy resistance and therefore act as a reservoir for secondary disease and leukemia relapse. In recent years, a number of studies have helped illuminate the complexity of clonality in bone marrow pathologies, including leukemias. Many features distinguishing LSCs from normal hematopoietic stem cells have been identified, and these studies have opened up diverse avenues for targeting LSCs, with an impact on the clinical management of AML patients. This review will discuss the role of self-renewal in AML and its implications, distinguishing characteristics between normal and leukemia stem cells, and opportunities for therapeutic targeting of AML LSCs.
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Affiliation(s)
- Karina Barbosa
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
| | - Aniruddha J. Deshpande
- Tumor Initiation and Maintenance Program, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
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19
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Darici S, Jørgensen HG, Huang X, Serafin V, Antolini L, Barozzi P, Luppi M, Forghieri F, Marmiroli S, Zavatti M. Improved efficacy of quizartinib in combination therapy with PI3K inhibition in primary FLT3-ITD AML cells. Adv Biol Regul 2023; 89:100974. [PMID: 37245251 DOI: 10.1016/j.jbior.2023.100974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2023] [Revised: 05/09/2023] [Accepted: 05/22/2023] [Indexed: 05/30/2023]
Abstract
Acute myeloid leukemia is a heterogeneous hematopoietic malignancy, characterized by uncontrolled clonal proliferation of abnormal myeloid progenitor cells, with poor outcomes. The internal tandem duplication (ITD) mutation of the Fms-like receptor tyrosine kinase 3 (FLT3) (FLT3-ITD) represents the most common genetic alteration in AML, detected in approximately 30% of AML patients, and is associated with high leukemic burden and poor prognosis. Therefore, this kinase has been regarded as an attractive druggable target for the treatment of FLT3-ITD AML, and selective small molecule inhibitors, such as quizartinib, have been identified and trialled. However, clinical outcomes have been disappointing so far due to poor remission rates, also because of acquired resistance. A strategy to overcome resistance is to combine FLT3 inhibitors with other targeted therapies. In this study, we investigated the preclinical efficacy of the combination of quizartinib with the pan PI3K inhibitor BAY-806946 in FLT3-ITD cell lines and primary cells from AML patients. We show here that BAY-806946 enhanced quizartinib cytotoxicity and, most importantly, that this combination increases the ability of quizartinib to kill CD34+ CD38-leukemia stem cells, whilst sparing normal hematopoietic stem cells. Because constitutively active FLT3 receptor tyrosine kinase is known to boost aberrant PI3K signaling, the increased sensitivity of primary cells to the above combination can be the mechanistic results of the disruption of signaling by vertical inhibition.
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Affiliation(s)
- Salihanur Darici
- Cellular Signaling Unit, Section of Human Morphology, Department of Biomedical, Metabolic and Neural Sciences, Largo del Pozzo 71, University of Modena and Reggio Emilia, Modena, 41125, Italy; Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - Heather G Jørgensen
- Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - Xu Huang
- Haemato-Oncology/Systems Medicine Group, Paul O'Gorman Leukaemia Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, G12 0ZD, UK
| | - Valentina Serafin
- Department of Surgery Oncology and Gastroenterology Oncology and Immunology Section University of Padova, Italy
| | - Ludovica Antolini
- Cellular Signaling Unit, Section of Human Morphology, Department of Biomedical, Metabolic and Neural Sciences, Largo del Pozzo 71, University of Modena and Reggio Emilia, Modena, 41125, Italy
| | - Patrizia Barozzi
- Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria Di Modena, Via del Pozzo 71, 41124, Modena, Italy
| | - Mario Luppi
- Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria Di Modena, Via del Pozzo 71, 41124, Modena, Italy.
| | - Fabio Forghieri
- Department of Medical and Surgical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria Di Modena, Via del Pozzo 71, 41124, Modena, Italy.
| | - Sandra Marmiroli
- Cellular Signaling Unit, Section of Human Morphology, Department of Biomedical, Metabolic and Neural Sciences, Largo del Pozzo 71, University of Modena and Reggio Emilia, Modena, 41125, Italy.
| | - Manuela Zavatti
- Cellular Signaling Unit, Section of Human Morphology, Department of Biomedical, Metabolic and Neural Sciences, Largo del Pozzo 71, University of Modena and Reggio Emilia, Modena, 41125, Italy
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20
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Antony ML, Chang D, Noble-Orcutt KE, Kay A, Jensen JL, Mohei H, Myers CL, Sachs K, Sachs Z. CD69 marks a subpopulation of acute myeloid leukemia with enhanced colony forming capacity and a unique signaling activation state. Leuk Lymphoma 2023; 64:1262-1274. [PMID: 37161853 DOI: 10.1080/10428194.2023.2207698] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 01/10/2023] [Accepted: 04/09/2023] [Indexed: 05/11/2023]
Abstract
In acute myeloid leukemia (AML), leukemia stem cells (LSCs) have self-renewal potential and are responsible for relapse. We previously showed that, in Mll-AF9/NRASG12V murine AML, CD69 expression marks an LSC-enriched subpopulation with enhanced in vivo self-renewal capacity. Here, we used CyTOF to define activated signaling pathways in LSC subpopulations in Mll-AF9/NRASG12V AML. Furthermore, we compared the signaling activation states of CD69High and CD36High subsets of primary human AML. The human CD69High subset expresses low levels of Ki67 and high levels of NFκB and pMAPKAPKII. Additionally, the human CD69High AML subset also has enhanced colony-forming capacity. We applied Bayesian network modeling to compare the global signaling network within the human AML subsets. We find that distinct signaling states, distinguished by NFκB and pMAPKAPKII levels, correlate with divergent functional subsets, defined by CD69 and CD36 expression, in human AML. Targeting NFκB with proteasome inhibition diminished colony formation.
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Affiliation(s)
- Marie Lue Antony
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Daniel Chang
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Klara E Noble-Orcutt
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Anna Kay
- University of Michigan Medical School, Ann Arbor, MI, USA
| | - Jeffrey L Jensen
- Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Hesham Mohei
- Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Chad L Myers
- Department of Computer Science and Engineering, University of Minnesota, Minneapolis, MN, USA
| | - Karen Sachs
- Next Generation Analytics, Palo Alto, CA, USA
| | - Zohar Sachs
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
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21
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Zhang H, Wu G, Chen B. Knockdown of neurotrophin receptor-interacting melanoma-associated antigen homolog inhibits acute myeloid leukemia cell growth via the ERK pathway. CHINESE J PHYSIOL 2023; 66:276-283. [PMID: 37635487 DOI: 10.4103/cjop.cjop-d-22-00162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023] Open
Abstract
Neurotrophin receptor-interacting melanoma-associated antigen homolog (NRAGE), a type II melanoma-associated antigen, plays a critical role in cell processes that are involved in the tumorigenesis of various cancers. However, the effect of NRAGE on acute myeloid leukemia (AML) is rarely reported. The expression of NRAGE in AML tissues and the survival rates between different AML groups were obtained from the GEPIA tool. Human AML cell lines were cultured and transfected with siRNA targeting NRAGE. The ability of AML cells to proliferate and cell cycle were examined. Western blotting was performed to detect the activity of the extracellular signal-regulated kinase (ERK) signaling pathway in AML cells. NRAGE expression was enhanced in AML tissues relative to control tissues, and the high NRAGE expression in AML patients is associated with a poor prognosis. The capacity of AML cells to survive and proliferate was significantly decreased and its cell cycle was arrested at the G1 phase after NRAGE was silenced. Furthermore, silencing NRAGE induced the inactivation of the ERK signaling pathway. Furthermore, supplement of tert-Butylhydroquinone, an ERK activator, improved the reduced ability of AML cell survival and proliferation as well as cell cycle arrest induced by NRAGE knockdown. In this study, NRAGE was identified as a tumor promoter in AML, which had an effect on cell proliferation, cell survival, and cell cycle through the ERK signaling pathway in AML cells.
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Affiliation(s)
- Hongxia Zhang
- Department of Hematology, First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang Uygur Autonomous Region, China
| | - Guangsheng Wu
- Department of Hematology, First Affiliated Hospital of Shihezi University, Shihezi, Xinjiang Uygur Autonomous Region, China
| | - Beili Chen
- Department of Hematological, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi Zhuang Autonomous Region, Guangxi, China
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22
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Pappalardo XG, Risiglione P, Zinghirino F, Ostuni A, Luciano D, Bisaccia F, De Pinto V, Guarino F, Messina A. Human VDAC pseudogenes: an emerging role for VDAC1P8 pseudogene in acute myeloid leukemia. Biol Res 2023; 56:33. [PMID: 37344914 DOI: 10.1186/s40659-023-00446-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 06/08/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND Voltage-dependent anion selective channels (VDACs) are the most abundant mitochondrial outer membrane proteins, encoded in mammals by three genes, VDAC1, 2 and 3, mostly ubiquitously expressed. As 'mitochondrial gatekeepers', VDACs control organelle and cell metabolism and are involved in many diseases. Despite the presence of numerous VDAC pseudogenes in the human genome, their significance and possible role in VDAC protein expression has not yet been considered. RESULTS We investigated the relevance of processed pseudogenes of human VDAC genes, both in physiological and in pathological contexts. Using high-throughput tools and querying many genomic and transcriptomic databases, we show that some VDAC pseudogenes are transcribed in specific tissues and pathological contexts. The obtained experimental data confirm an association of the VDAC1P8 pseudogene with acute myeloid leukemia (AML). CONCLUSIONS Our in-silico comparative analysis between the VDAC1 gene and its VDAC1P8 pseudogene, together with experimental data produced in AML cellular models, indicate a specific over-expression of the VDAC1P8 pseudogene in AML, correlated with a downregulation of the parental VDAC1 gene.
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Affiliation(s)
- Xena Giada Pappalardo
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123, Catania, Italy
| | - Pierpaolo Risiglione
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123, Catania, Italy
| | - Federica Zinghirino
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123, Catania, Italy
| | - Angela Ostuni
- Department of Sciences, University of Basilicata, 85100, Potenza, Italy
| | - Daniela Luciano
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123, Catania, Italy
| | - Faustino Bisaccia
- Department of Sciences, University of Basilicata, 85100, Potenza, Italy
| | - Vito De Pinto
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123, Catania, Italy
- we.MitoBiotech S.R.L, C.so Italia 172, 95125, Catania, Italy
- I.N.B.B, National Institute for Biostructures and Biosystems, Interuniversity Consortium, Catania, Italy
- Research Centre on Nutraceuticals and Health Products (CERNUT), University of Catania, 95125, Catania, Italy
| | - Francesca Guarino
- Department of Biomedical and Biotechnological Sciences, University of Catania, Via Santa Sofia 97, 95123, Catania, Italy
- we.MitoBiotech S.R.L, C.so Italia 172, 95125, Catania, Italy
- I.N.B.B, National Institute for Biostructures and Biosystems, Interuniversity Consortium, Catania, Italy
- Research Centre on Nutraceuticals and Health Products (CERNUT), University of Catania, 95125, Catania, Italy
| | - Angela Messina
- we.MitoBiotech S.R.L, C.so Italia 172, 95125, Catania, Italy.
- I.N.B.B, National Institute for Biostructures and Biosystems, Interuniversity Consortium, Catania, Italy.
- Research Centre on Nutraceuticals and Health Products (CERNUT), University of Catania, 95125, Catania, Italy.
- Department of Biological, Geological and Environmental Sciences, University of Catania, Via Santa Sofia 97, 95123, Catania, Italy.
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23
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Li Q, Wang M, Liu L. The role of exosomes in the stemness maintenance and progression of acute myeloid leukemia. Biochem Pharmacol 2023; 212:115539. [PMID: 37024061 DOI: 10.1016/j.bcp.2023.115539] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2023] [Revised: 03/17/2023] [Accepted: 03/29/2023] [Indexed: 04/08/2023]
Abstract
Acute myeloid leukemia (AML) is an aggressive malignancy of myeloid hematopoietic cells, which is characterized by the aberrant clonal proliferation of immature myeloblasts and compromised hematopoiesis. The leukemic cell population is strongly heterogeneous. Leukemic stem cells (LSCs) are an important leukemic cell subset with stemness characteristics and self-renewal ability, which contribute to the development of refractory or relapsed AML. It is now acknowledged that LSCs develop from hematopoietic stem cells (HSCs) or phenotypically directed cell populations with transcriptional stemness characteristics under selective pressure from the bone marrow (BM) niche. Exosomes are extracellular vesicles containing bioactive substances involved in intercellular communication and material exchange under steady state and pathological conditions. Several studies have reported that exosomes mediate molecular crosstalk between LSCs, leukemic blasts, and stromal cells in the BM niche, promoting LSC maintenance and AML progression. This review briefly describes the process of LSC transformation and the biogenesis of exosomes, highlighting the role of leukemic-cell- and BM-niche-derived exosomes in the maintenance of LSCs and AML progression. In addition, we discuss the potential application of exosomes in the clinic as biomarkers, therapeutic targets, and carriers for targeted drug delivery.
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Affiliation(s)
- Qian Li
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Mengyuan Wang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Lingbo Liu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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24
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Zheng X, Wu J, Song L, Huang B. ACSM3 suppresses proliferation and induces apoptosis and cell cycle arrest in acute myeloid leukemia cells via the regulation of IGF2BP2. Exp Ther Med 2023; 25:177. [PMID: 37006876 PMCID: PMC10061044 DOI: 10.3892/etm.2023.11876] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 10/07/2022] [Indexed: 03/11/2023] Open
Abstract
Acyl-CoA medium-chain synthetase-3 (ACSM3) has been reported to be involved in the malignant progression of multiple types of human cancer. Nevertheless, the role of ACSM3 in acute myeloid leukemia (AML) and its exact mechanism of action are as yet undefined. In the present study, the expression levels of ACSM3 and IGF2 mRNA-binding protein 2 (IGF2BP2) were evaluated using the Gene Expression Profiling Interactive Analysis database and AML cells. The Cell Counting Kit-8 assay and 5-ethynyl-2'-deoxyuridine staining were employed for the estimation of the cell proliferative activity. Induction of apoptosis and the assessment of the cell cycle were measured using flow cytometry and western blotting, respectively. The interaction of ACSM3 with IGF2BP2 was confirmed using an RNA immunoprecipitation assay. mRNA stabilization of ACSM3 following actinomycin D treatment was evaluated using reverse transcription-quantitative PCR analysis. The data indicated that the expression levels of ACSM3 were significantly downregulated, whereas those of IGF2BP2 were upregulated in tissues and AML cells. Downregulation of ACSM3 expression was closely associated with poor overall survival of patients with AML. ACSM3 overexpression repressed cell proliferative activity and induced apoptosis and cell cycle arrest. IGF2BP2 downregulated ACSM3 expression by reducing the stability of ACSM3 mRNA. In addition, IGF2BP2 overexpression counteracted the effects of ACSM3 overexpression noted on proliferation, induction of apoptosis and cell cycle arrest of HL-60 cells. In conclusion, ACSM3 repressed the cell proliferative activity and facilitated induction of apoptosis and cell cycle arrest in AML cells by modulating the expression of IGF2BP2.
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Affiliation(s)
- Xin Zheng
- Department of Clinical Laboratory, Jianghan Oilfield General Hospital of Changjiang University, Qianjiang, Hubei 433124, P.R. China
| | - Jinjun Wu
- Department of Clinical Laboratory, Jianghan Oilfield General Hospital of Changjiang University, Qianjiang, Hubei 433124, P.R. China
| | - Linlan Song
- Department of Clinical Laboratory, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710004, P.R. China
| | - Bo Huang
- Department of Clinical Laboratory, The Affiliated Children Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710003, P.R. China
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25
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Anderson NR, Sheth V, Li H, Harris MW, Qiu S, Crossman DK, Kumar H, Agarwal P, Nagasawa T, Paterson AJ, Welner RS, Bhatia R. Microenvironmental CXCL12 deletion enhances Flt3-ITD acute myeloid leukemia stem cell response to therapy by reducing p38 MAPK signaling. Leukemia 2023; 37:560-570. [PMID: 36550214 PMCID: PMC10750268 DOI: 10.1038/s41375-022-01798-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Revised: 12/07/2022] [Accepted: 12/12/2022] [Indexed: 12/24/2022]
Abstract
Fms-like tyrosine kinase 3 (Flt3) tyrosine kinase inhibitors (Flt3-TKI) have improved outcomes for patients with Flt3-mutated acute myeloid leukemia (AML) but are limited by resistance and relapse, indicating persistence of leukemia stem cells (LSC). Here utilizing a Flt3-internal tandem duplication (Flt3-ITD) and Tet2-deleted AML genetic mouse model we determined that FLT3-ITD AML LSC were enriched within the primitive ST-HSC population. FLT3-ITD LSC showed increased expression of the CXCL12 receptor CXCR4. CXCL12-abundant reticular (CAR) cells were increased in Flt3-ITD AML marrow. CXCL12 deletion from the microenvironment enhanced targeting of AML cells by Flt3-TKI plus chemotherapy treatment, including enhanced LSC targeting. Both treatment and CXCL12 deletion partially reduced p38 mitogen-activated protein kinase (p38) signaling in AML cells and further reduction was seen after treatment in CXCL12 deleted mice. p38 inhibition reduced CXCL12-dependent and -independent maintenance of both murine and human Flt3-ITD AML LSC by MSC and enhanced their sensitivity to treatment. p38 inhibition in combination with chemotherapy plus TKI treatment leads to greater depletion of Flt3-ITD AML LSC compared with CXCL12 deletion. Our studies support roles for CXCL12 and p38 signaling in microenvironmental protection of AML LSC and provide a rationale for inhibiting p38 signaling to enhance Flt3-ITD AML targeting.
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Affiliation(s)
- Nicholas R Anderson
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Vipul Sheth
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Hui Li
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Mason W Harris
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Shaowei Qiu
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Tianjin, China
| | - David K Crossman
- Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Harish Kumar
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Puneet Agarwal
- Division of Experimental Hematology & Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Takashi Nagasawa
- Laboratory of Stem Cell Biology & Developmental Immunology, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan
| | - Andrew J Paterson
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Robert S Welner
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Ravi Bhatia
- Division of Hematology and Oncology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
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26
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Liang L, Kaufmann AM. The Significance of Cancer Stem Cells and Epithelial-Mesenchymal Transition in Metastasis and Anti-Cancer Therapy. Int J Mol Sci 2023; 24:ijms24032555. [PMID: 36768876 PMCID: PMC9917228 DOI: 10.3390/ijms24032555] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Cancer stem cells (CSCs) have been identified and characterized in both hematopoietic and solid tumors. Their existence was first predicted by Virchow and Cohnheim in the 1870s. Later, many studies showed that CSCs can be identified and isolated by their expression of specific cell markers. The significance of CSCs with respect to tumor biology and anti-cancer treatment lies in their ability to maintain quiescence with very slow proliferation, indefinite self-renewal, differentiation, and trans-differentiation such as epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET). The ability for detachment, migration, extra- and intravasation, invasion and thereby of completing all necessary steps of the metastatic cascade highlights their significance for metastasis. CSCs comprise the cancer cell populations responsible for tumor growth, resistance to therapies and cancer metastasis. In this review, the history of the CSC theory, their identification and characterization and their biology are described. The contribution of the CSC ability to undergo EMT for cancer metastasis is discussed. Recently, novel strategies for drug development have focused on the elimination of the CSCs specifically. The unique functional and molecular properties of CSCs are discussed as possible therapeutic vulnerabilities for the development of novel anti-metastasis treatments. Prospectively, this may provide precise personalized anti-cancer treatments with improved therapeutic efficiency with fewer side effects and leading to better prognosis.
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27
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Wu J, Deng Y, Zhang X, Ma J, Zheng X, Chen Y. Suchilactone inhibits the growth of acute myeloid leukaemia by inactivating SHP2. PHARMACEUTICAL BIOLOGY 2022; 60:144-153. [PMID: 34962431 PMCID: PMC8725822 DOI: 10.1080/13880209.2021.2017467] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 12/07/2021] [Indexed: 05/12/2023]
Abstract
CONTEXT Suchilactone, a lignan compound extracted from Monsonia angustifolia E.Mey. ex A.Rich. (Geraniaceae), has little research on pharmacological activity; whether suchilactone has inhibitory effect on acute myeloid leukaemia (AML) is unclear. OBJECTIVE To investigate the antitumor effect of suchilactone and its mechanism in AML. MATERIALS AND METHODS The effects of suchilactone on cell growth were detected by CCK-8 and flow cytometry. Network pharmacology was conducted to explore target of suchilactone. Gene expression was detected by western blot and RT-PCR. SHI-1 cells (1 × 106 cell per mouse) were subcutaneously inoculated into the female SCID mice. Suchilactone (15 and 30 mg/kg) was dissolved in PBS with 0.5% carboxymethylcellulose sodium and administered (i.g.) to mice once a day for 19 days, while the control group received PBS with 0.5% carboxymethylcellulose sodium. Tumour tissues were stained with Ki-67 and TUNEL. RESULTS Suchilactone exerted an effective inhibition on the growth of SHI-1 cells with IC50 of 17.01 μM. Then, we found that suchilactone binds to the SHP2 protein and inhibits its activation, and suchilactone interacted with SHP2 to inhibit cell proliferation and promote cell apoptosis via blocking the activation of SHP2. Moreover, Suchilaction inhibited tumour growth of AML xenografts in mice, as the tumour weight decreased from 0.618 g (control) to 0.35 g (15 mg/kg) and 0.258 g (30 mg/kg). Suchilactone inhibited Ki-67 expression and increased TUNEL expression in tumour tissue. DISCUSSION AND CONCLUSIONS Our study is the first to demonstrate suchilactone inhibits AML growth, suggesting that suchilactone is a candidate drug for the treatment of AML.
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MESH Headings
- Animals
- Female
- Humans
- Mice
- Antineoplastic Agents, Phytogenic/administration & dosage
- Antineoplastic Agents, Phytogenic/isolation & purification
- Antineoplastic Agents, Phytogenic/pharmacology
- Apoptosis/drug effects
- Cell Line, Tumor
- Cell Proliferation/drug effects
- Dose-Response Relationship, Drug
- Geraniaceae/chemistry
- Leukemia, Myeloid, Acute/drug therapy
- Mice, Inbred BALB C
- Mice, SCID
- Network Pharmacology
- Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Jingjing Wu
- Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai’an, China
| | - Yuan Deng
- Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai’an, China
| | - Xin Zhang
- Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai’an, China
| | - Jingjing Ma
- Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai’an, China
| | - Xinqi Zheng
- Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai’an, China
| | - Yue Chen
- Department of Hematology, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, Huai’an, China
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28
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Davies DM, van den Handel K, Bharadwaj S, Lengefeld J. Cellular enlargement - A new hallmark of aging? Front Cell Dev Biol 2022; 10:1036602. [PMID: 36438561 PMCID: PMC9688412 DOI: 10.3389/fcell.2022.1036602] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 10/17/2022] [Indexed: 12/03/2023] Open
Abstract
Years of important research has revealed that cells heavily invest in regulating their size. Nevertheless, it has remained unclear why accurate size control is so important. Our recent study using hematopoietic stem cells (HSCs) in vivo indicates that cellular enlargement is causally associated with aging. Here, we present an overview of these findings and their implications. Furthermore, we performed a broad literature analysis to evaluate the potential of cellular enlargement as a new aging hallmark and to examine its connection to previously described aging hallmarks. Finally, we highlight interesting work presenting a correlation between cell size and age-related diseases. Taken together, we found mounting evidence linking cellular enlargement to aging and age-related diseases. Therefore, we encourage researchers from seemingly unrelated areas to take a fresh look at their data from the perspective of cell size.
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Affiliation(s)
- Daniel M. Davies
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Kim van den Handel
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Soham Bharadwaj
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
| | - Jette Lengefeld
- Institute of Biotechnology, HiLIFE, University of Helsinki, Helsinki, Finland
- Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden
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29
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Li J, Wu Y, Wang M, Chen X, Li Z, Bai X, Wu H. MicroRNA-1306-5p Regulates the METTL14-Guided m6A Methylation to Repress Acute Myeloid Leukemia. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:5787808. [PMID: 36118827 PMCID: PMC9473907 DOI: 10.1155/2022/5787808] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 08/19/2022] [Accepted: 08/22/2022] [Indexed: 11/17/2022]
Abstract
miRNA and m6A methylation are two key regulators in cancers. However, in acute myeloid leukemia (AML), the relationship of miRNA and m6A methylation remains unclear. The present work is aimed at determining the effect of m6A methylation induced by miRNAs on AML and its underlying mechanism. The expression of METTL14 was detected by qRT-PCR and western blot. The growth of HL-60 cells was analyzed by CCK-8, Transwell assay, and flow cytometry. Tumor-bearing mice were established, and Ki-67 staining assay was used to detect the proliferation in vivo. Dual luciferase reporter system detected the effect of miR-1306-5p on METTL14 luciferase activity. Dot blot analysis detected m6A methylation. We found that METTL14 was upregulated in AML patients and overexpressed METTL14 promoted AML development. Further analysis indicated that METTL14 was directly targeted by miR-1306-5p and overexpressed miR-1306-5p alleviated AML progression. In addition, m6A methylation level regulated by METTL14 could be affected by miR-1306-5p. In conclusion, we found that suppressed miR-1306-5p enhanced AML progression by elevating m6A methylation level via upregulating METTL14. These findings provided basis for the development of new strategies for treating AML.
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Affiliation(s)
- Jiajia Li
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Yanping Wu
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Meng Wang
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Xiaofeng Chen
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Zhongyu Li
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Xue Bai
- Department of Hematology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui, China
| | - Haotian Wu
- Bengbu Medical College, Bengbu, Anhui, China
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30
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Ung J, Tan SF, Fox TE, Shaw JJP, Vass LR, Costa-Pinheiro P, Garrett-Bakelman FE, Keng MK, Sharma A, Claxton DF, Levine RL, Tallman MS, Cabot MC, Kester M, Feith DJ, Loughran TP. Harnessing the power of sphingolipids: Prospects for acute myeloid leukemia. Blood Rev 2022; 55:100950. [PMID: 35487785 PMCID: PMC9475810 DOI: 10.1016/j.blre.2022.100950] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/31/2022] [Accepted: 04/04/2022] [Indexed: 11/02/2022]
Abstract
Acute myeloid leukemia (AML) is an aggressive, heterogenous malignancy characterized by clonal expansion of bone marrow-derived myeloid progenitor cells. While our current understanding of the molecular and genomic landscape of AML has evolved dramatically and opened avenues for molecularly targeted therapeutics to improve upon standard intensive induction chemotherapy, curative treatments are elusive, particularly in older patients. Responses to current AML treatments are transient and incomplete, necessitating the development of novel treatment strategies to improve outcomes. To this end, harnessing the power of bioactive sphingolipids to treat cancer shows great promise. Sphingolipids are involved in many hallmarks of cancer of paramount importance in AML. Leukemic blast survival is influenced by cellular levels of ceramide, a bona fide pro-death molecule, and its conversion to signaling molecules such as sphingosine-1-phosphate and glycosphingolipids. Preclinical studies demonstrate the efficacy of therapeutics that target dysregulated sphingolipid metabolism as well as their combinatorial synergy with clinically-relevant therapeutics. Thus, increased understanding of sphingolipid dysregulation may be exploited to improve AML patient care and outcomes. This review summarizes the current knowledge of dysregulated sphingolipid metabolism in AML, evaluates how pro-survival sphingolipids promote AML pathogenesis, and discusses the therapeutic potential of targeting these dysregulated sphingolipid pathways.
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Affiliation(s)
- Johnson Ung
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; University of Virginia Cancer Center, Charlottesville, VA, United States of America
| | - Su-Fern Tan
- Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; University of Virginia Cancer Center, Charlottesville, VA, United States of America
| | - Todd E Fox
- University of Virginia Cancer Center, Charlottesville, VA, United States of America; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, United States of America
| | - Jeremy J P Shaw
- University of Virginia Cancer Center, Charlottesville, VA, United States of America; Department of Experimental Pathology, University of Virginia School of Medicine, Charlottesville, VA, United States of America
| | - Luke R Vass
- University of Virginia Cancer Center, Charlottesville, VA, United States of America; Department of Experimental Pathology, University of Virginia School of Medicine, Charlottesville, VA, United States of America
| | - Pedro Costa-Pinheiro
- Cancer Biology, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Francine E Garrett-Bakelman
- Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; University of Virginia Cancer Center, Charlottesville, VA, United States of America; Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine, Charlottesville, VA, United States of America
| | - Michael K Keng
- Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; University of Virginia Cancer Center, Charlottesville, VA, United States of America
| | - Arati Sharma
- Penn State Cancer Institute, Hershey, PA, United States of America
| | - David F Claxton
- Penn State Cancer Institute, Hershey, PA, United States of America
| | - Ross L Levine
- Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Martin S Tallman
- Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Myles C Cabot
- Department of Biochemistry and Molecular Biology, East Carolina University, Brody School of Medicine, Greenville, NC, United States of America; East Carolina Diabetes and Obesity Institute, East Carolina University, Brody School of Medicine, Greenville, NC, United States of America
| | - Mark Kester
- University of Virginia Cancer Center, Charlottesville, VA, United States of America; Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, United States of America
| | - David J Feith
- Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; University of Virginia Cancer Center, Charlottesville, VA, United States of America
| | - Thomas P Loughran
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; Division of Hematology/Oncology, University of Virginia School of Medicine, Charlottesville, VA, United States of America; University of Virginia Cancer Center, Charlottesville, VA, United States of America.
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lncRNA GAS5 Induces Cell Apoptosis in Acute Myeloid Leukemia by Targeting Nrf2. DISEASE MARKERS 2022; 2022:5178122. [PMID: 36061350 PMCID: PMC9433261 DOI: 10.1155/2022/5178122] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/03/2022] [Revised: 07/11/2022] [Accepted: 07/28/2022] [Indexed: 11/17/2022]
Abstract
Objective This study is aimed at investigating the molecular mechanism of lncRNA GAS5-induced cell apoptosis in acute myeloid leukemia (AML) by targeting Nrf2. Methods The RNA interfering technique was utilized to silence THP-1 in AML cell line, and lncRNA GAS5 expression in cell line was determined by real-time PCR. EdU experiment and flow cytometry were used to detect the apoptosis and proliferation ability of cells in different groups. PD-L1, STAT3, AKT, and MMP9 expressions were determined by Western blot. Results The si-RNA significantly inhibited the expression of lncRNA GAS5 in THP-1 cells. Compared with the si-NC group, the difference in cell apoptosis between lncRNA GAS5 and Nrf2 groups was significant (P < 0.05). Compared with the lncRNA GAS5 group, the number of apoptotic cells in the lncRNA GAS5+Nrf2 group significantly reduced (P < 0.05). Compared with the si-NC group, the differences in the levels of four proteins between lncRNA GAS5 and Nrf2 groups were significant (P < 0.05). In lncRNA GAS5+Nrf2 and lncRNA GAS5 groups, PD-L1 expression increased, while the expression of STAT3, AKT, and MMP9 decreased. Conclusion In AML cells, lncRNA GAS5 with Nrf2 could regulate the proliferation and apoptosis of AML cells. lncRNA GAS5 inhibited Nrf2 expression, regulated cell apoptosis and proliferation, and further inhibited the progression of AML disease.
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Dozzo A, Galvin A, Shin JW, Scalia S, O'Driscoll CM, Ryan KB. Modelling acute myeloid leukemia (AML): What's new? A transition from the classical to the modern. Drug Deliv Transl Res 2022:10.1007/s13346-022-01189-4. [PMID: 35930221 DOI: 10.1007/s13346-022-01189-4] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/24/2022] [Indexed: 11/24/2022]
Abstract
Acute myeloid leukemia (AML) is a heterogeneous malignancy affecting myeloid cells in the bone marrow (BM) but can spread giving rise to impaired hematopoiesis. AML incidence increases with age and is associated with poor prognostic outcomes. There has been a disconnect between the success of novel drug compounds observed in preclinical studies of hematological malignancy and less than exceptional therapeutic responses in clinical trials. This review aims to provide a state-of-the-art overview on the different preclinical models of AML available to expand insights into disease pathology and as preclinical screening tools. Deciphering the complex physiological and pathological processes and developing predictive preclinical models are key to understanding disease progression and fundamental in the development and testing of new effective drug treatments. Standard scaffold-free suspension models fail to recapitulate the complex environment where AML occurs. To this end, we review advances in scaffold/matrix-based 3D models and outline the most recent advances in on-chip technology. We also provide an overview of clinically relevant animal models and review the expanding use of patient-derived samples, which offer the prospect to create more "patient specific" screening tools either in the guise of 3D matrix models, microphysiological "organ-on-chip" tools or xenograft models and discuss representative examples.
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Affiliation(s)
| | - Aoife Galvin
- School of Pharmacy, University College Cork, Cork, Ireland
| | - Jae-Won Shin
- Department of Pharmacology and Regenerative Medicine, University of Illinois at Chicago College of Medicine, 909 S. Wolcott Ave, Chicago, IL, 5091 COMRB, USA
| | - Santo Scalia
- Università degli Studi di Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy
| | - Caitriona M O'Driscoll
- School of Pharmacy, University College Cork, Cork, Ireland.,SSPC Centre for Pharmaceutical Research, School of Pharmacy, University College Cork, Cork, Ireland
| | - Katie B Ryan
- School of Pharmacy, University College Cork, Cork, Ireland. .,SSPC Centre for Pharmaceutical Research, School of Pharmacy, University College Cork, Cork, Ireland.
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33
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Barreto IV, Pessoa FMCDP, Machado CB, Pantoja LDC, Ribeiro RM, Lopes GS, Amaral de Moraes ME, de Moraes Filho MO, de Souza LEB, Burbano RMR, Khayat AS, Moreira-Nunes CA. Leukemic Stem Cell: A Mini-Review on Clinical Perspectives. Front Oncol 2022; 12:931050. [PMID: 35814466 PMCID: PMC9270022 DOI: 10.3389/fonc.2022.931050] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 05/25/2022] [Indexed: 11/13/2022] Open
Abstract
Hematopoietic stem cells (HSCs) are known for their ability to proliferate and self-renew, thus being responsible for sustaining the hematopoietic system and residing in the bone marrow (BM). Leukemic stem cells (LSCs) are recognized by their stemness features such as drug resistance, self-renewal, and undifferentiated state. LSCs are also present in BM, being found in only 0.1%, approximately. This makes their identification and even their differentiation difficult since, despite the mutations, they are cells that still have many similarities with HSCs. Although the common characteristics, LSCs are heterogeneous cells and have different phenotypic characteristics, genetic mutations, and metabolic alterations. This whole set of alterations enables the cell to initiate the process of carcinogenesis, in addition to conferring drug resistance and providing relapses. The study of LSCs has been evolving and its application can help patients, where through its count as a biomarker, it can indicate a prognostic factor and reveal treatment results. The selection of a target to LSC therapy is fundamental. Ideally, the target chosen should be highly expressed by LSCs, highly selective, absence of expression on other cells, in particular HSC, and preferentially expressed by high numbers of patients. In view of the large number of similarities between LSCs and HSCs, it is not surprising that current treatment approaches are limited. In this mini review we seek to describe the immunophenotypic characteristics and mechanisms of resistance presented by LSCs, also approaching possible alternatives for the treatment of patients.
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Affiliation(s)
- Igor Valentim Barreto
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
| | - Flávia Melo Cunha de Pinho Pessoa
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
| | - Caio Bezerra Machado
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
| | - Laudreísa da Costa Pantoja
- Department of Pediatrics, Octávio Lobo Children’s Hospital, Belém, Brazil
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém, Brazil
| | | | | | - Maria Elisabete Amaral de Moraes
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
| | - Manoel Odorico de Moraes Filho
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
| | | | | | - André Salim Khayat
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém, Brazil
| | - Caroline Aquino Moreira-Nunes
- Department of Medicine, Pharmacogenetics Laboratory, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, Brazil
- Department of Biological Sciences, Oncology Research Center, Federal University of Pará, Belém, Brazil
- Ceará State University, Northeast Biotechnology Network (RENORBIO), Fortaleza, Brazil
- *Correspondence: Caroline Aquino Moreira-Nunes,
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Dissecting the Genetic and Non-Genetic Heterogeneity of Acute Myeloid Leukemia Using Next-Generation Sequencing and In Vivo Models. Cancers (Basel) 2022; 14:cancers14092182. [PMID: 35565315 PMCID: PMC9103951 DOI: 10.3390/cancers14092182] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 04/21/2022] [Accepted: 04/25/2022] [Indexed: 02/01/2023] Open
Abstract
Simple Summary Acute myeloid leukemia (AML) is an extremely aggressive form of blood cancer with high rates of treatment failure. AML arises from the stepwise acquisition of genetic aberrations and is a highly heterogeneous disorder. Recent research has shown that individual AML samples often contain several clones that are defined by a distinct combination of genetic lesions, epigenetic patterns and cell surface marker expression profiles. A better understanding of the clonal dynamics of AML is required to develop novel treatment strategies against this disease. In this review, we discuss the recent developments that have further deepened our understanding of clonal evolution and heterogeneity in AML. Abstract Acute myeloid leukemia (AML) is an extremely aggressive and heterogeneous disorder that results from the transformation of hematopoietic stem cells. Although our understanding of the molecular pathology of AML has greatly improved in the last few decades, the overall and relapse free survival rates among AML patients remain quite poor. This is largely due to evolution of the disease and selection of the fittest, treatment-resistant leukemic clones. There is increasing evidence that most AMLs possess a highly complex clonal architecture and individual leukemias are comprised of genetically, phenotypically and epigenetically distinct clones, which are continually evolving. Advances in sequencing technologies as well as studies using murine AML models have provided further insights into the heterogeneity of leukemias. We will review recent advances in the field of genetic and non-genetic heterogeneity in AML.
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35
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Stucky A, Gao L, Li SC, Tu L, Luo J, Huang X, Chen X, Li X, Park TH, Cai J, Kabeer MH, Plant AS, Sun L, Zhang X, Zhong JF. Molecular Characterization of Differentiated-Resistance MSC Subclones by Single-Cell Transcriptomes. Front Cell Dev Biol 2022; 10:699144. [PMID: 35356283 PMCID: PMC8959432 DOI: 10.3389/fcell.2022.699144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Accepted: 02/14/2022] [Indexed: 11/25/2022] Open
Abstract
Background: The mechanism of tumorigenicity potentially evolved in mesenchymal stem cells (MSCs) remains elusive, resulting in inconsistent clinical application efficacy. We hypothesized that subclones in MSCs contribute to their tumorgenicity, and we approached MSC-subclones at the single-cell level. Methods: MSCs were cultured in an osteogenic differentiation medium and harvested on days 12, 19, and 25 for cell differentiation analysis using Alizarin Red and followed with the single-cell transcriptome. Results: Single-cell RNA-seq analysis reveals a discrete cluster of MSCs during osteogenesis, including differentiation-resistant MSCs (DR-MSCs), differentiated osteoblasts (DO), and precursor osteoblasts (PO). The DR-MSCs population resembled cancer initiation cells and were subjected to further analysis of the yes associated protein 1 (YAP1) network. Verteporfin was also used for YAP1 inhibition in cancer cell lines to confirm the role of YAP1 in MSC--involved tumorigenicity. Clinical data from various cancer types were analyzed to reveal relationships among YAP1, OCT4, and CDH6 in MSC--involved tumorigenicity. The expression of cadherin 6 (CDH6), octamer-binding transcription factor 4 (OCT4), and YAP1 expression was significantly upregulated in DR-MSCs compared to PO and DO. YAP1 inhibition by Verteporfin accelerated the differentiation of MSCs and suppressed the expression of YAP1, CDH6, and OCT4. A survey of 56 clinical cohorts revealed a high degree of co-expression among CDH6, YAP1, and OCT4 in various solid tumors. YAP1 inhibition also down-regulated HeLa cell viability and gradually inhibited YAP1 nuclear localization while reducing the transcription of CDH6 and OCT4. Conclusions: We used single-cell sequencing to analyze undifferentiated MSCs and to discover a carcinogenic pathway in single-cell MSCs of differentiated resistance subclones.
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Affiliation(s)
- Andres Stucky
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, CA, United States
| | - Li Gao
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Shengwen Calvin Li
- Neuro-oncology and Stem Cell Research Laboratory, CHOC Children’s Research Institute, Center for Neuroscience Research, Children’s Hospital of Orange County (CHOC), Orange, CA, United States
- Department of Neurology, Irvine School of Medicine, University of California, Irvine, CA, United States
| | - Lingli Tu
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, CA, United States
- Department of Oncology, Bishan, The People’s Hospital of Bishan District, Bishan, Chongqing, China
| | - Jun Luo
- Stomatological Hospital of Chongqing Medical University, Chongqing, China
| | - Xi Huang
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xuelian Chen
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, CA, United States
| | - Xiaoqing Li
- Department of Oncology, Bishan, The People’s Hospital of Bishan District, Bishan, Chongqing, China
| | - Tiffany H. Park
- School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Jin Cai
- Department of Oral and Maxillofacial Surgery, Zhuhai People’s Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, China
| | - Mustafa H. Kabeer
- Pediatric Surgery, CHOC Children’s Hospital, Department of Surgery, Irvine School of Medicine, University of California, Irvine, CA, United States
| | - Ashley S. Plant
- Division of Pediatric Oncology, Children’s Hospital of Orange County, Orange, CA, United States
| | - Lan Sun
- Department of Oncology, Bishan, The People’s Hospital of Bishan District, Bishan, Chongqing, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital, Army Medical University, Chongqing, China
| | - Jiang F. Zhong
- Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California, CA, United States
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Mesbahi Y, Trahair TN, Lock RB, Connerty P. Exploring the Metabolic Landscape of AML: From Haematopoietic Stem Cells to Myeloblasts and Leukaemic Stem Cells. Front Oncol 2022; 12:807266. [PMID: 35223487 PMCID: PMC8867093 DOI: 10.3389/fonc.2022.807266] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Accepted: 01/18/2022] [Indexed: 12/13/2022] Open
Abstract
Despite intensive chemotherapy regimens, up to 60% of adults with acute myeloid leukaemia (AML) will relapse and eventually succumb to their disease. Recent studies suggest that leukaemic stem cells (LSCs) drive AML relapse by residing in the bone marrow niche and adapting their metabolic profile. Metabolic adaptation and LSC plasticity are novel hallmarks of leukemogenesis that provide important biological processes required for tumour initiation, progression and therapeutic responses. These findings highlight the importance of targeting metabolic pathways in leukaemia biology which might serve as the Achilles' heel for the treatment of AML relapse. In this review, we highlight the metabolic differences between normal haematopoietic cells, bulk AML cells and LSCs. Specifically, we focus on four major metabolic pathways dysregulated in AML; (i) glycolysis; (ii) mitochondrial metabolism; (iii) amino acid metabolism; and (iv) lipid metabolism. We then outline established and emerging drug interventions that exploit metabolic dependencies of leukaemic cells in the treatment of AML. The metabolic signature of AML cells alters during different biological conditions such as chemotherapy and quiescence. Therefore, targeting the metabolic vulnerabilities of these cells might selectively eradicate them and improve the overall survival of patients with AML.
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Affiliation(s)
- Yashar Mesbahi
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,University of New South Wales Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
| | - Toby N Trahair
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia
| | - Richard B Lock
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,University of New South Wales Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
| | - Patrick Connerty
- Children's Cancer Institute, Lowy Cancer Centre, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,School of Women's and Children's Health, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia.,University of New South Wales Centre for Childhood Cancer Research, University of New South Wales (UNSW) Sydney, Kensington, NSW, Australia
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37
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Wang SY, Hu QC, Wu T, Xia J, Tao XA, Cheng B. Abnormal lipid synthesis as a therapeutic target for cancer stem cells. World J Stem Cells 2022; 14:146-162. [PMID: 35432735 PMCID: PMC8963380 DOI: 10.4252/wjsc.v14.i2.146] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/19/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.
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Affiliation(s)
- Si-Yu Wang
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Qin-Chao Hu
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Tong Wu
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Juan Xia
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Xiao-An Tao
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Bin Cheng
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
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Nachmias B, Khan DH, Voisin V, Mer AS, Thomas GE, Segev N, St-Germain J, Hurren R, Gronda M, Botham A, Wang X, Maclean N, Seneviratne AK, Duong N, Xu C, Arruda A, Orouji E, Algouneh A, Hakem R, Shlush L, Minden MD, Raught B, Bader GD, Schimmer AD. IPO11 regulates the nuclear import of BZW1/2 and is necessary for AML cells and stem cells. Leukemia 2022; 36:1283-1295. [PMID: 35152270 PMCID: PMC9061300 DOI: 10.1038/s41375-022-01513-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Revised: 01/06/2022] [Accepted: 01/26/2022] [Indexed: 12/24/2022]
Abstract
AML cells are arranged in a hierarchy with stem/progenitor cells giving rise to more differentiated bulk cells. Despite the importance of stem/progenitors in the pathogenesis of AML, the determinants of the AML stem/progenitor state are not fully understood. Through a comparison of genes that are significant for growth and viability of AML cells by way of a CRISPR screen, with genes that are differentially expressed in leukemia stem cells (LSC), we identified importin 11 (IPO11) as a novel target in AML. Importin 11 (IPO11) is a member of the importin β family of proteins that mediate transport of proteins across the nuclear membrane. In AML, knockdown of IPO11 decreased growth, reduced engraftment potential of LSC, and induced differentiation. Mechanistically, we identified the transcription factors BZW1 and BZW2 as novel cargo of IPO11. We further show that BZW1/2 mediate a transcriptional signature that promotes stemness and survival of LSC. Thus, we demonstrate for the first time how specific cytoplasmic-nuclear regulation supports stem-like transcriptional signature in relapsed AML.
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LncRNA UCA1 Promotes the Progression of AML by Upregulating the Expression of CXCR4 and CYP1B1 by Affecting the Stability of METTL14. JOURNAL OF ONCOLOGY 2022; 2022:2756986. [PMID: 35178087 PMCID: PMC8847036 DOI: 10.1155/2022/2756986] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Accepted: 01/18/2022] [Indexed: 12/12/2022]
Abstract
Objective. Increasing numbers of studies have proved that m6A methylation plays crucial roles in different cancers. However, how lncRNA regulates m6A methylation and participates in acute myeloid leukemia (AML) remains unclear. Therefore, this study aims to explore the function and mechanism of UCA1 in AML by regulating m6A methylation. Methods. qRT-PCR, western blot, and immunohistochemical staining were used to detect the expression of METTL14, CXCR4, and CYP1B1. qRT-PCR was used to detect the expression of UCA1. CCK8, flow cytometry, and transwell assays were used to detect the proliferation, apoptosis, migration, and invasion of HL60 and U937 cells, respectively. m6A methylation was detected by dot blot analysis. Tumor-bearing mice were established, and tumor weight and volume were analyzed. Immunofluorescence staining, co-localization, and RNA pull-down were used to confirm the reaction between UCA1 and METTL14. Results. Overexpression of UCA1 promotes AML development in vitro. Furthermore, we found that METTL14-influenced m6A methylation could be affected by UCA1. UCA1 promoted AML development by regulating m6A methylation. Moreover, the expression of CYP1B1 and CXCR4 was affected by METTL14. In addition, UCA1 promoted AML development by affecting m6A methylation in vivo. Conclusion. In the present study, we demonstrated that lncRNAUCA1 promotes the progression of AML by upregulating the expression of CXCR4 and CYP1B1 by affecting the stability of METTL14.
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Fodil S, Arnaud M, Vaganay C, Puissant A, Lengline E, Mooney N, Itzykson R, Zafrani L. Endothelial cells: major players in acute myeloid leukaemia. Blood Rev 2022; 54:100932. [DOI: 10.1016/j.blre.2022.100932] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 01/27/2022] [Accepted: 01/28/2022] [Indexed: 12/17/2022]
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Zhang Y, Liu D, Li F, Zhao Z, Liu X, Gao D, Zhang Y, Li H. Identification of biomarkers for acute leukemia via machine learning-based stemness index. Gene 2021; 804:145903. [PMID: 34411647 DOI: 10.1016/j.gene.2021.145903] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Revised: 07/20/2021] [Accepted: 08/12/2021] [Indexed: 12/13/2022]
Abstract
Traditional methods to understand leukemia stem cell (LSC)'s biological characteristics include constructing LSC-like cells and mouse models by transgenic or knock-in methods. However, there are some potential pitfalls in using this method, such as retroviral insertion mutagenesis, non-physiological level gene expression, non-physiological expansion, and difficulty to construct. The mRNAsi index for each sample of the Cancer Genome Atlas (TCGA) could avoid these potential pitfalls by machine learning. In this work, we aimed to construct a network of LSC genes utilizing the mRNAsi. First, mRNAsi value was analyzed with expressions distributions, survival analysis, age, and gender in acute myeloid leukemia (AML) samples. Then, we used the weighted gene co-expression network analysis (WGCNA) to construct modules of stemness genes. The correlation of the LSC genes transcription and interplay among LSC proteins was analyzed. We performed functional and pathway enrichment analysis to annotate stemness genes. Survival analysis further identified prognostic biomarkers by clinical data of TCGA and the Gene Expression Omnibus (GEO) database. We found that the result of mRNAsi overall survival is not significant, which may be due to the heterogeneity of AML in the stage of myeloid differentiation, French-American-British (FAB) classification systems. Enrichment analysis indicated that the stemness genes were biologically clustered as a group and mainly associated with cell cycle and mitosis. Moreover, 10 key genes (SNRNP40, RFC4, RFC5, CDC6, HSPE1, PA2G4, SNAP23P, DARS2, MIS18A, and HPRT1) were screened by survival analysis with the data from TCGA and GEO. Among them, RFC4 and RFC5 were the distinguished biomarkers for their double-validated prognostic value in both databases. Additionally, the expression of RFC4 and RFC5 had the same trend as mRNAsi score in FAB subtypes. In conclusion, our result demonstrated that mRNAsi based LSC-related genes were found to have strong interactions as a cluster. These genes, especially RFC4 and RFC5, could be the therapeutic targets for inhibiting the stemness characteristics of AML. This work is also a comprehensive pipeline for future cancer stem cell studies.
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Affiliation(s)
- Yitong Zhang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin 150081, China
| | - Dongzhe Liu
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin 150081, China; Department of Hematology and Oncology, International Cancer Center, Shenzhen Key Laboratory, Shenzhen University General Hospital, Shenzhen University Clinical Medical Academy, Shenzhen University Health Science Center, Xueyuan AVE 1098, Shenzhen 518000, China
| | - Fenglan Li
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin 150081, China
| | - Zihui Zhao
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin 150081, China
| | - Xiqing Liu
- The State Key Laboratory of Networking and Switching Technology, Beijing University of Posts and Telecommunications, Beijing 100876, China
| | - Dixiang Gao
- School of Information and Communication Engineering, Beijing University of Posts and Telecommunications, Beijing 100876, China
| | - Yutong Zhang
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin 150081, China
| | - Hui Li
- Department of Biochemistry and Molecular Biology, Harbin Medical University, Harbin 150081, China.
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Welte T, Mai J, Zhang Z, Tian S, Zhang G, Xu Y, Zhang L, Chen SS, Wang T, Shen H. A heparan-sulfate-bearing syndecan-1 glycoform is a distinct surface marker for intra-tumoral myeloid-derived suppressor cells. iScience 2021; 24:103349. [PMID: 34825135 PMCID: PMC8603209 DOI: 10.1016/j.isci.2021.103349] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Revised: 09/17/2021] [Accepted: 10/22/2021] [Indexed: 11/19/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) infiltrate cancer tissue, promote tumor growth, and are associated with resistance to cancer therapies. However, there is no practical approach available to distinguish MDSCs from mature counterparts inside tumors. Here, we show that a recently isolated thioaptamer probe (T1) binds to MDSC subsets in colorectal and pancreatic tumors with high specificity. Whole transcriptome and functional analysis revealed that T1-binding cells contain polymorphonuclear (PMN)-MDSCs characterized by several immunosuppression pathways, ROS production, and T cell suppression activity, whereas T1-non-binding PMNs were mature and nonsuppressive. We identified syndecan-1 as the T1-interacting protein on MDSCs and chronic myelogenous leukemia K562 cell line. Heparan sulfate chains were essential in T1-binding. Inside tumors PMN-MDSCs expressed heparan sulfate biogenesis enzymes at higher levels. Tumor-cell-derived soluble factor(s) enhanced MDSCs' affinity for T1. Overall, we uncovered heparan-sulfate-dependent MDSC modulation in the tumor microenvironment and identified T1 as tool preferentially targeting tumor-promoting myeloid cell subsets.
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Affiliation(s)
- Thomas Welte
- Department of Nanomedicine, Houston Methodist Academic Institute, Houston, TX 77030, USA
| | - Junhua Mai
- Department of Nanomedicine, Houston Methodist Academic Institute, Houston, TX 77030, USA
| | - Zhe Zhang
- Department of Nanomedicine, Houston Methodist Academic Institute, Houston, TX 77030, USA
| | - Shaohui Tian
- Department of Nanomedicine, Houston Methodist Academic Institute, Houston, TX 77030, USA
| | - Guodong Zhang
- Department of Nanomedicine, Houston Methodist Academic Institute, Houston, TX 77030, USA
| | - Yitian Xu
- Center for Immunotherapy Research, Houston Methodist Academic Institute, Houston, TX 77030, USA
| | - Licheng Zhang
- Center for Immunotherapy Research, Houston Methodist Academic Institute, Houston, TX 77030, USA
| | - Shu-shia Chen
- Center for Immunotherapy Research, Houston Methodist Academic Institute, Houston, TX 77030, USA
| | - Tian Wang
- Department of Microbiology & Immunology, The University of Texas Medical Branch, 301 University Boulevard, Galveston, TX 77555, USA
| | - Haifa Shen
- Department of Nanomedicine, Houston Methodist Academic Institute, Houston, TX 77030, USA
- Innovative Therapeutic Program, Houston Methodist Cancer Center, Houston, TX 77030, USA
- Department of Cell and Developmental Biology, Weill Cornell Medicine, New York, NY 10065, USA
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43
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Bolandi SM, Pakjoo M, Beigi P, Kiani M, Allahgholipour A, Goudarzi N, Khorashad JS, Eiring AM. A Role for the Bone Marrow Microenvironment in Drug Resistance of Acute Myeloid Leukemia. Cells 2021; 10:2833. [PMID: 34831055 PMCID: PMC8616250 DOI: 10.3390/cells10112833] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2021] [Revised: 10/13/2021] [Accepted: 10/14/2021] [Indexed: 02/08/2023] Open
Abstract
Acute myeloid leukemia (AML) is a heterogeneous disease with a poor prognosis and remarkable resistance to chemotherapeutic agents. Understanding resistance mechanisms against currently available drugs helps to recognize the therapeutic obstacles. Various mechanisms of resistance to chemotherapy or targeted inhibitors have been described for AML cells, including a role for the bone marrow niche in both the initiation and persistence of the disease, and in drug resistance of the leukemic stem cell (LSC) population. The BM niche supports LSC survival through direct and indirect interactions among the stromal cells, hematopoietic stem/progenitor cells, and leukemic cells. Additionally, the BM niche mediates changes in metabolic and signal pathway activation due to the acquisition of new mutations or selection and expansion of a minor clone. This review briefly discusses the role of the BM microenvironment and metabolic pathways in resistance to therapy, as discovered through AML clinical studies or cell line and animal models.
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Affiliation(s)
- Seyed Mohammadreza Bolandi
- Department of Immunology, Razi Vaccine and Sera Research Institute, Karaj, Iran; (S.M.B.); (N.G.)
- Department of Pharmacology, Karaj Branch, Islamic Azad University, Karaj, Iran; (M.K.); (A.A.)
| | - Mahdi Pakjoo
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; (M.P.); (P.B.)
| | - Peyman Beigi
- Department of Hematology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; (M.P.); (P.B.)
| | - Mohammad Kiani
- Department of Pharmacology, Karaj Branch, Islamic Azad University, Karaj, Iran; (M.K.); (A.A.)
| | - Ali Allahgholipour
- Department of Pharmacology, Karaj Branch, Islamic Azad University, Karaj, Iran; (M.K.); (A.A.)
| | - Negar Goudarzi
- Department of Immunology, Razi Vaccine and Sera Research Institute, Karaj, Iran; (S.M.B.); (N.G.)
| | - Jamshid S. Khorashad
- Centre for Haematology, Hammersmith Hospital, Imperial College London, London W12 0HS, UK;
| | - Anna M. Eiring
- Center of Emphasis in Cancer, Department of Molecular and Translational Medicine, Texas Tech University Health Sciences Center at El Paso, El Paso, TX 79905, USA
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López-Cortés A, Abarca E, Silva L, Velastegui E, León-Sosa A, Karolys G, Cabrera F, Caicedo A. Identification of key proteins in the signaling crossroads between wound healing and cancer hallmark phenotypes. Sci Rep 2021; 11:17245. [PMID: 34446793 PMCID: PMC8390472 DOI: 10.1038/s41598-021-96750-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2021] [Accepted: 07/20/2021] [Indexed: 02/07/2023] Open
Abstract
Wound healing (WH) and cancer seem to share common cellular and molecular processes that could work in a tight balance to maintain tissue homeostasis or, when unregulated, drive tumor progression. The "Cancer Hallmarks" comprise crucial biological properties that mediate the advancement of the disease and affect patient prognosis. These hallmarks have been proposed to overlap with essential features of the WH process. However, common hallmarks and proteins actively participating in both processes have yet to be described. In this work we identify 21 WH proteins strongly linked with solid tumors by integrated TCGA Pan-Cancer and multi-omics analyses. These proteins were associated with eight of the ten described cancer hallmarks, especially avoiding immune destruction. These results show that WH and cancer's common proteins are involved in the microenvironment modification of solid tissues and immune system regulation. This set of proteins, between WH and cancer, could represent key targets for developing therapies.
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Affiliation(s)
- Andrés López-Cortés
- grid.412257.70000 0004 0485 6316Facultad de Ciencias de la Salud Eugenio Espejo, Universidad UTE, Quito, Ecuador ,Latin American Network for the Implementation and Validation of Clinical Pharmacogenomics Guidelines (RELIVAF-CYTED), Madrid, Spain ,grid.8073.c0000 0001 2176 8535RNASA-IMEDIR, Computer Science Faculty, Universidad of A Coruna, A Coruña, Spain
| | - Estefanía Abarca
- grid.442129.8Carrera de Biotecnología, Universidad Politécnica Salesiana UPS, Quito, Ecuador
| | - Leonardo Silva
- grid.442129.8Carrera de Biotecnología, Universidad Politécnica Salesiana UPS, Quito, Ecuador
| | - Erick Velastegui
- grid.442129.8Carrera de Biotecnología, Universidad Politécnica Salesiana UPS, Quito, Ecuador
| | - Ariana León-Sosa
- grid.412251.10000 0000 9008 4711Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Germania Karolys
- grid.442129.8Carrera de Biotecnología, Universidad Politécnica Salesiana UPS, Quito, Ecuador ,grid.442129.8Grupo de Investigación y Desarrollo en Ciencias Aplicadas a los Recursos Biológicos, Universidad Politécnica Salesiana, Quito, Ecuador
| | - Francisco Cabrera
- grid.412251.10000 0000 9008 4711Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador ,grid.412251.10000 0000 9008 4711Colegio de Ciencias de la Salud, Escuela de Medicina Veterinaria, Universidad San Francisco de Quito USFQ, Quito, Ecuador
| | - Andrés Caicedo
- grid.412251.10000 0000 9008 4711Instituto de Investigaciones en Biomedicina iBioMed, Universidad San Francisco de Quito USFQ, Quito, Ecuador ,grid.412251.10000 0000 9008 4711Colegio de Ciencias de la Salud, Escuela de Medicina, Universidad San Francisco de Quito USFQ, Quito, Ecuador ,Mito-Act Research Consortium, Quito, Ecuador ,grid.412251.10000 0000 9008 4711Sistemas Médicos SIME, Universidad San Francisco de Quito USFQ, Quito, Ecuador
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45
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Panicker S, Venkatabalasubramanian S, Pathak S, Ramalingam S. The impact of fusion genes on cancer stem cells and drug resistance. Mol Cell Biochem 2021; 476:3771-3783. [PMID: 34095988 DOI: 10.1007/s11010-021-04203-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 05/29/2021] [Indexed: 12/12/2022]
Abstract
With ever increasing evidences on the role of fusion genes as the oncogenic protagonists in myriad cancers, it's time to explore if fusion genes can be the next generational drug targets in meeting the current demands of higher drug efficacy. Eliminating cancer stem cells (CSC) has become the current focus; however, we have reached a standstill in drug development owing to the lack of effective strategies to eradicate CSC. We believe that fusion genes could be the novel targets to overcome this limitation. The intriguing feature of fusion genes is that it dominantly impacts every aspect of CSC including self-renewal, differentiation, lineage commitment, tumorigenicity and stemness. Given the clinical success of fusion gene-based drugs in hematological cancers, our attempt to target fusion genes in eradicating CSC can be rewarding. As fusion genes are expressed explicitly in cancer cells, eradicating CSC by targeting fusion genes provides yet an another advantage of negligible patient side effects since normal cells remain unaffected by the drug. We hereby delineate the latest evidences on how fusion genes regulate CSC and drug resistance.
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Affiliation(s)
- Saurav Panicker
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Kanchipuram, 603203, Tamil Nadu, India
| | | | - Surajit Pathak
- Faculty of Allied Health Sciences, Chettinad Academy of Research and Education, Kelambakkam, Chennai, 603103, Tamil Nadu, India
| | - Satish Ramalingam
- Department of Genetic Engineering, SRM Institute of Science and Technology, Kattankulathur, Kanchipuram, 603203, Tamil Nadu, India.
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46
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Mohan A, Raj R R, Mohan G, K P P, Thomas Maliekal T. Reporters of Cancer Stem Cells as a Tool for Drug Discovery. Front Oncol 2021; 11:669250. [PMID: 33968778 PMCID: PMC8100607 DOI: 10.3389/fonc.2021.669250] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 03/29/2021] [Indexed: 01/04/2023] Open
Abstract
In view of the importance of cancer stem cells (CSCs) in chemoresistance, metastasis and recurrence, the biology of CSCs were explored in detail. Based on that, several modalities were proposed to target them. In spite of the several clinical trials, a successful CSC-targeting drug is yet to be identified. The number of molecules screened and entered for clinical trial for CSC-targeting is comparatively low, compared to other drugs. The bottle neck is the lack of a high-throughput adaptable screening strategy for CSCs. This review is aimed to identify suitable reporters for CSCs that can be used to identify the heterogeneous CSC populations, including quiescent CSCs, proliferative CSCs, drug resistant CSCs and metastatic CSCs. Analysis of the tumor microenvironment regulating CSCs revealed that the factors in CSC-niche activates effector molecules that function as CSC markers, including pluripotency markers, CD133, ABCG2 and ALDH1A1. Among these factors OCT4, SOX2, NANOG, ABCG2 and ALDH1A1 are ideal for making reporters for CSCs. The pluripotency molecules, like OCT4, SOX2 and NANOG, regulate self-renewal, chemoresistance and metastasis. ABCG2 is a known regulator of drug resistance while ALDH1A1 modulates self-renewal, chemoresistance and metastasis. Considering the heterogeneity of CSCs, including a quiescent population and a proliferative population with metastatic ability, we propose the use of a combination of reporters. A dual reporter consisting of a pluripotency marker and a marker like ALDH1A1 will be useful in screening drugs that target CSCs.
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Affiliation(s)
- Amrutha Mohan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India.,Centre for Doctoral Studies, Manipal Academy of Higher Education, Manipal, India
| | - Reshma Raj R
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Gayathri Mohan
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Padmaja K P
- Cancer Research, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
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47
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Li Y, Li Y, Yin J, Wang C, Yang M, Gu J, He M, Xu H, Fu W, Zhang W, Ru Y, Liu X, Li Y, Xin Y, Gao H, Xie X, Gao Y. A mitophagy inhibitor targeting p62 attenuates the leukemia-initiation potential of acute myeloid leukemia cells. Cancer Lett 2021; 510:24-36. [PMID: 33862150 DOI: 10.1016/j.canlet.2021.04.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 03/06/2021] [Accepted: 04/04/2021] [Indexed: 12/20/2022]
Abstract
There has been an increasing focus on the tumorigenic potential of leukemia initiating cells (LICs) in acute myeloid leukemia (AML). Despite the important role of selective autophagy in the life-long maintenance of hematopoietic stem cells (HSCs), cancer progression, and chemoresistance, the relationship between LICs and selective autophagy remains to be fully elucidated. Sequestosome 1 (SQSTM1), also known as p62, is a selective autophagy receptor for the degradation of ubiquitinated substrates, and its loss impairs leukemia progression in AML mouse models. In this study, we evaluated the underlying mechanisms of mitophagy in the survival of LICs with XRK3F2, a p62-ZZ inhibitor. We demonstrated that XRK3F2 selectively impaired LICs but spared normal HSCs in both mouse and patient-derived tumor xenograft (PDX) AML models. Mechanistically, we observed that XRK3F2 blocked mitophagy by inhibiting the binding of p62 with defective mitochondria. Our study not only evaluated the effectiveness and safety of XRK3F2 in LICs, but also demonstrated that mitophagy plays an indispensable role in the survival of LICs during AML development and progression, which can be impaired by blocking p62.
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Affiliation(s)
- Yinghui Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Yafang Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Jingjing Yin
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Chaoqun Wang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Ming Yang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Jiali Gu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Mei He
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Hui Xu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Weichao Fu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Wenshan Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Yongxin Ru
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Xiaolei Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China
| | - Ying Li
- Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Yue Xin
- Key Laboratory of Post-Neuroinjury Neuro-repair and Regeneration in Central Nervous System, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Huier Gao
- Department of Pharmacy, Tianjin First Central Hospital, School of Medicine, Nankai University, Tianjin, 300192, China
| | - Xiangqun Xie
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, NIH National Center of Excellence for Computational Drug Abuse Research, Drug Discovery Institute; Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15260, United States.
| | - Yingdai Gao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, PUMC Department of Stem Cell and Regenerative Medicine, CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
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48
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Lainez-González D, Serrano-López J, Alonso-Domínguez JM. Understanding the Hedgehog Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Necessary Step toward a Cure. BIOLOGY 2021; 10:biology10040255. [PMID: 33804919 PMCID: PMC8063837 DOI: 10.3390/biology10040255] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/17/2021] [Accepted: 03/23/2021] [Indexed: 12/12/2022]
Abstract
Simple Summary The Hedgehog signaling pathway is related to the cell cycle. In particular, it is considered to play a fundamental role in the quiescence of leukemic stem cell (i.e., a temporary resting state without cell replication). Leukemic stem cells are the cells supposed to give rise to the relapses of the leukemia. Therefore, the Hedgehog pathway must be understood to improve the current treatments against acute myeloid leukemia and avoid the relapse of the disease. In this review, we gather the present knowledge about the physiological Hedgehog pathway function, the aberrant activation of Hedgehog in leukemia, and highlight the lack of evidence regarding some aspects of this important pathway. Finally, we summarize the acute myeloid leukemia treatments targeting this signaling pathway. Abstract A better understanding of how signaling pathways govern cell fate is fundamental to advances in cancer development and treatment. The initialization of different tumors and their maintenance are caused by the deregulation of different signaling pathways and cancer stem cell maintenance. Quiescent stem cells are resistant to conventional chemotherapeutic treatments and, consequently, are responsible for disease relapse. In this review we focus on the conserved Hedgehog (Hh) signaling pathway which is involved in regulating the cell cycle of hematopoietic and leukemic stem cells. Thus, we examine the role of the Hh signaling pathway in normal and leukemic stem cells and dissect its role in acute myeloid leukemia. We explain not only the connection between illness and the signaling pathway but also evaluate innovative therapeutic approaches that could affect the outcome of patients with acute myeloid leukemia. We found that many aspects of the Hedgehog signaling pathway remain unknown. The role of Hh has only been proven in embryo and hematopoietic stem cell development. Further research is needed to elucidate the role of GLI transcription factors for therapeutic targeting. Glasdegib, an SMO inhibitor, has shown clinical activity in acute myeloid leukemia; however, its mechanism of action is not clear.
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Affiliation(s)
- Daniel Lainez-González
- Experimental Hematology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain; (D.L.-G.); (J.S.-L.)
| | - Juana Serrano-López
- Experimental Hematology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain; (D.L.-G.); (J.S.-L.)
| | - Juan Manuel Alonso-Domínguez
- Experimental Hematology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain; (D.L.-G.); (J.S.-L.)
- Hematology Department, Hospital Universitario Fundación Jiménez Díaz, Avenida Reyes Católicos 2, 28040 Madrid, Spain
- Correspondence: ; Tel.: +34-918488100-2673
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49
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Deak D, Gorcea-Andronic N, Sas V, Teodorescu P, Constantinescu C, Iluta S, Pasca S, Hotea I, Turcas C, Moisoiu V, Zimta AA, Galdean S, Steinheber J, Rus I, Rauch S, Richlitzki C, Munteanu R, Jurj A, Petrushev B, Selicean C, Marian M, Soritau O, Andries A, Roman A, Dima D, Tanase A, Sigurjonsson O, Tomuleasa C. A narrative review of central nervous system involvement in acute leukemias. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:68. [PMID: 33553361 PMCID: PMC7859772 DOI: 10.21037/atm-20-3140] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Acute leukemias (both myeloid and lymphoblastic) are a group of diseases for which each year more successful therapies are implemented. However, in a subset of cases the overall survival (OS) is still exceptionally low due to the infiltration of leukemic cells in the central nervous system (CNS) and the subsequent formation of brain tumors. The CNS involvement is more common in acute lymphocytic leukemia (ALL), than in adult acute myeloid leukemia (AML), although the rates for the second case might be underestimated. The main reasons for CNS invasion are related to the expression of specific adhesion molecules (VLA-4, ICAM-1, VCAM, L-selectin, PECAM-1, CD18, LFA-1, CD58, CD44, CXCL12) by a subpopulation of leukemic cells, called “sticky cells” which have the ability to interact and adhere to endothelial cells. Moreover, the microenvironment becomes hypoxic and together with secretion of VEGF-A by ALL or AML cells the permeability of vasculature in the bone marrow increases, coupled with the disruption of blood brain barrier. There is a single subpopulation of leukemia cells, called leukemia stem cells (LSCs) that is able to resist in the new microenvironment due to its high adaptability. The LCSs enter into the arachnoid, migrate, and intensively proliferate in cerebrospinal fluid (CSF) and consequently infiltrate perivascular spaces and brain parenchyma. Moreover, the CNS is an immune privileged site that also protects leukemic cells from chemotherapy. CD56/NCAM is the most important surface molecule often overexpressed by leukemic stem cells that offers them the ability to infiltrate in the CNS. Although asymptomatic or with unspecific symptoms, CNS leukemia should be assessed in both AML/ALL patients, through a combination of flow cytometry and cytological analysis of CSF. Intrathecal therapy (ITT) is a preventive measure for CNS involvement in AML and ALL, still much research is needed in finding the appropriate target that would dramatically lower CNS involvement in acute leukemia.
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Affiliation(s)
- Dalma Deak
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania.,Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Nicolae Gorcea-Andronic
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Valentina Sas
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Department of Pediatrics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Patric Teodorescu
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania.,Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Catalin Constantinescu
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Intensive Care Unit, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania
| | - Sabina Iluta
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania.,Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Sergiu Pasca
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania.,Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ionut Hotea
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania.,Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristina Turcas
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania.,Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Vlad Moisoiu
- Department of Neurosurgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Alina-Andreea Zimta
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Simona Galdean
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania
| | - Jakob Steinheber
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ioana Rus
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania
| | - Sebastian Rauch
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cedric Richlitzki
- Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Raluca Munteanu
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Ancuta Jurj
- Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Bobe Petrushev
- Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Cristina Selicean
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania
| | - Mirela Marian
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania
| | - Olga Soritau
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania
| | - Alexandra Andries
- Department of Radiology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania
| | - Andrei Roman
- Department of Radiology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania.,Department of Radiology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
| | - Delia Dima
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania
| | - Alina Tanase
- Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | | | - Ciprian Tomuleasa
- Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania.,Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.,Medfuture Research Center for Advanced Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
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Profiling of Metabolic Differences between Hematopoietic Stem Cells and Acute/Chronic Myeloid Leukemia. Metabolites 2020; 10:metabo10110427. [PMID: 33114596 PMCID: PMC7692247 DOI: 10.3390/metabo10110427] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 10/22/2020] [Accepted: 10/22/2020] [Indexed: 02/07/2023] Open
Abstract
Although many studies have been conducted on leukemia, only a few have analyzed the metabolomic profiles of various leukemic cells. In this study, the metabolomes of THP-1, U937, KG-1 (acute myelogenous leukemia, AML), K562 (chronic myelogenous leukemia, CML), and cord blood-derived CD34-positive hematopoietic stem cells (HSC) were analyzed using gas chromatography-mass spectrometry, and specific metabolic alterations were found using multivariate statistical analysis. Compared to HSCs, leukemia cell metabolomes were found to have significant alterations, among which three were related to amino acids, three to sugars, and five to fatty acids. Compared to CML, four metabolomes were observed specifically in AML. Given that overall more metabolites are present in leukemia cells than in HSCs, we observed that the activation of glycolysis and oxidative phosphorylation (OXPHOS) metabolism facilitated the incidence of leukemia and the proliferation of leukemic cells. Analysis of metabolome profiles specifically present in HSCs and leukemia cells greatly increases our basic understanding of cellular metabolic characteristics, which is valuable fundamental knowledge for developing novel anticancer drugs targeting leukemia metabolism.
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