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Wagstaff M, Sevim O, Goff A, Raynor M, Park H, Mancini EJ, Nguyen DTT, Chevassut T, Blair A, Castellano L, Newbury S, Towler B, Morgan RG. β-Catenin interacts with canonical RBPs including MSI2 to associate with a Wnt signalling mRNA network in myeloid leukaemia cells. Oncogene 2025:10.1038/s41388-025-03415-y. [PMID: 40301545 DOI: 10.1038/s41388-025-03415-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2025] [Revised: 04/02/2025] [Accepted: 04/09/2025] [Indexed: 05/01/2025]
Abstract
Wnt/β-catenin signalling is important for normal hematopoietic stem/progenitor cell (HSPC) biology and heavily implicated in acute and chronic myeloid leukaemia (AML and CML). The central mediator β-catenin is an attractive therapeutic target in myeloid neoplasms however its targeting has been hampered by a poor characterisation of its molecular interactions in haematopoietic cells, which will differ from its network in solid tissues. Our previous β-catenin interactome study identified the significant enrichment of RNA-binding proteins (RBP) implying post-transcriptional roles for β-catenin in myeloid cells. To identify β-catenin interacting mRNAs we performed β-catenin RNA-immunoprecipitation coupled to RNA-sequencing (RIP-seq) and identified significantly enriched Wnt signalling pathway transcripts. Using β-catenin cross-linking immunoprecipitation (CLIP) we demonstrated a limited capacity for β-catenin to bind RNA directly, implying dependence on other RBPs. β-Catenin was found to interact with Musashi-2 (MSI2) in both myeloid cell lines and primary AML patient samples, where expression was significantly correlated. MSI2 knockdown reduced Wnt signalling output (TCF/LEF activity), through suppression of LEF-1 expression and nuclear localisation. Through both RIP and CLIP we demonstrate MSI2 binds LEF1 mRNA in a partly β-catenin dependent fashion, and may impact the post-transcriptional control of LEF-1 expression. Finally, we show that MSI2-mediated expansion of human HSPCs could be partly driven through LEF1 regulation. This is the first study to experimentally demonstrate functional crosstalk between MSI2 and Wnt signalling in human cells, and indicates potential novel post-transcriptional roles for β-catenin in a haematological context.
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Affiliation(s)
- M Wagstaff
- School of Life Sciences, University of Sussex, Brighton, UK
| | - O Sevim
- School of Life Sciences, University of Sussex, Brighton, UK
| | - A Goff
- School of Life Sciences, University of Sussex, Brighton, UK
| | - M Raynor
- Leeds Institute of Medical Research, Next Generation Sequencing Facility, University of Leeds, Leeds, UK
| | - H Park
- Brighton & Sussex Medical School, University of Sussex, Brighton, UK
- University Hospitals Sussex NHS Foundation Trust, Brighton, UK
| | - E J Mancini
- School of Life Sciences, University of Sussex, Brighton, UK
| | - D T T Nguyen
- Centre for Haemato-oncology, Cancer Research UK Barts Centre, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - T Chevassut
- Brighton & Sussex Medical School, University of Sussex, Brighton, UK
- University Hospitals Sussex NHS Foundation Trust, Brighton, UK
| | - A Blair
- Bristol Institute for Transfusion Sciences, NHS Blood & Transplant, Bristol, UK
| | - L Castellano
- School of Life Sciences, University of Sussex, Brighton, UK
- Department of Surgery and Cancer, Division of Cancer, Imperial Centre for Translational and Experimental Medicine (ICTEM), Imperial College London, London, UK
| | - S Newbury
- Brighton & Sussex Medical School, University of Sussex, Brighton, UK
| | - B Towler
- School of Life Sciences, University of Sussex, Brighton, UK
| | - R G Morgan
- School of Life Sciences, University of Sussex, Brighton, UK.
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2
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Wan H, Zhang YX, Shan GY, Cheng JY, Qiao DR, Liu YY, Shi WN, Li HJ. Antiviral therapy for hepatitis B virus infection is beneficial for the prognosis hepatocellular carcinoma. World J Gastrointest Oncol 2025; 17:93983. [PMID: 39817121 PMCID: PMC11664622 DOI: 10.4251/wjgo.v17.i1.93983] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Revised: 09/20/2024] [Accepted: 09/29/2024] [Indexed: 12/12/2024] Open
Abstract
In this editorial, we comment on the article by Mu et al, published in the recent issue of the World Journal of Gastrointestinal Oncology. We pay special attention to the immune tolerance mechanism caused by hepatitis B virus (HBV) infection, the pathogenesis of hepatocellular carcinoma (HCC), and the role of antiviral therapy in treating HCC related to HBV infection. HBV infection leads to systemic innate immune tolerance by directly inhibiting pattern recognition receptor recognition and antiviral signaling pathways, as well as by inhibiting the immune functions of macrophages, natural killer cells and dendritic cells. In addition, HBV leads to an immunosuppressive cascade by expressing inhibitory molecules to induce exhaustion of HBV-specific cluster of differentiation 8 + T cells, ultimately leading to long-term viral infection. The loss of immune cell function caused by HBV infection ultimately leads to HCC. Long-term antiviral therapy can improve the prognosis of patients with HCC and prevent tumor recurrence and metastasis.
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Affiliation(s)
- Hui Wan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Yu-Xin Zhang
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Guan-Yue Shan
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
| | - Jun-Ya Cheng
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Duan-Rui Qiao
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Yi-Ying Liu
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Wen-Na Shi
- Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
- Department of Bioengineering, Pharmacy School of Jilin University, Changchun 130061, Jilin Province, China
| | - Hai-Jun Li
- Institute of Liver Diseases, Institute of Translational Medicine, The First Hospital of Jilin University, Changchun 130061, Jilin Province, China
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Ide AD, Carpenter KA, Elaswad M, Opria K, Marcellin K, Gilliland C, Grainger S. Secreted Frizzled-Related Protein 1a regulates hematopoietic development in a dose-dependent manner. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.10.632371. [PMID: 39829913 PMCID: PMC11741364 DOI: 10.1101/2025.01.10.632371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/22/2025]
Abstract
Hematopoietic stem and progenitor cells (HSPCs) arise only during embryonic development, and their identity specification, emergence from the floor of the dorsal aorta, and proliferation are all tightly regulated by molecular mechanisms such as signaling cues. Among these, Wnt signaling plays an important role in HSPC specification, differentiation, and self-renewal, requiring precise modulation for proper development and homeostasis. Wnt signaling is initiated when a Wnt ligand binds to cell surface receptors such as those encoded by the frizzled gene family, activating intracellular signaling pathways that regulate gene expression. Secreted frizzled-related proteins (Sfrps) are known modulators of Wnt signaling, acting as both agonists and antagonists of this pathway. Yet, in vivo functions of Sfrps in HSPC development remain incompletely understood. Here, we demonstrate that Sfrp1a regulates zebrafish HSPC development and differentiation in a dose-dependent manner. In Sfrp1a loss of function animals, we observe an increase in HSPCs, an upregulation of canonical Wnt signaling, and a decrease in differentiation into both lymphoid and myeloid lineages. Conversely, at low-dose sfrp1a overexpression, there is a decrease in HSPCs and an increase in lymphoid differentiation. High-dose sfrp1a overexpression phenocopies the loss of function animals, with an increase in HSPCs, increased canonical Wnt signaling, and decreased lymphoid and myeloid differentiation. These findings highlight the importance of dose-dependent modulation of Sfrps, paralleling what is observed in hematopoietic cancers where SFRP1 loss-of-function and gain-of-function variants can drive tumorigenesis.
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Affiliation(s)
- Amber D. Ide
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, 49503, USA RRID: SCR_021956
| | - Kelsey A. Carpenter
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, 49503, USA RRID: SCR_021956
| | - Mohamed Elaswad
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, 49503, USA RRID: SCR_021956
| | - Katherine Opria
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, 49503, USA RRID: SCR_021956
| | - Kendersley Marcellin
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, 49503, USA RRID: SCR_021956
| | - Carla Gilliland
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, 49503, USA RRID: SCR_021956
| | - Stephanie Grainger
- Department of Cell Biology, Van Andel Institute, Grand Rapids, Michigan, 49503, USA RRID: SCR_021956
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Serio B, Giudice V, Selleri C. All Roads Lead to Interferon-γ: From Known to Untraveled Pathways in Acquired Aplastic Anemia. MEDICINA (KAUNAS, LITHUANIA) 2023; 59:2170. [PMID: 38138273 PMCID: PMC10744863 DOI: 10.3390/medicina59122170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 12/08/2023] [Accepted: 12/12/2023] [Indexed: 12/24/2023]
Abstract
Bone marrow failure (BMF) syndromes are a heterogeneous group of benign hematological conditions with common clinical features including reduced bone marrow cellularity and peripheral blood cytopenias. Acquired aplastic anemia (AA) is caused by T helper(Th)1-mediated immune responses and cytotoxic CD8+ T cell-mediated autologous immune attacks against hematopoietic stem and progenitor cells (HSPCs). Interferon-γ (IFNγ), tumor necrosis factor-α, and Fas-ligand are historically linked to AA pathogenesis because they drive Th1 and cytotoxic T cell-mediated responses and can directly induce HSPC apoptosis and differentiation block. The use of omics technologies has amplified the amount of data at the single-cell level, and knowledge on AA, and new scenarios, have been opened on "old" point of view. In this review, we summarize the current state-of-art of the pathogenic role of IFNγ in AA from initial findings to novel evidence, such as the involvement of the HIF-1α pathway, and how this knowledge can be translated in clinical practice.
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Affiliation(s)
- Bianca Serio
- Department of Medicine, Surgery, and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (B.S.); (C.S.)
| | - Valentina Giudice
- Department of Medicine, Surgery, and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (B.S.); (C.S.)
- Hematology and Transplant Center, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy
| | - Carmine Selleri
- Department of Medicine, Surgery, and Dentistry “Scuola Medica Salernitana”, University of Salerno, 84081 Baronissi, Italy; (B.S.); (C.S.)
- Hematology and Transplant Center, University Hospital “San Giovanni di Dio e Ruggi d’Aragona”, 84131 Salerno, Italy
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Srinivasan J, Vasudev A, Shasha C, Selden HJ, Perez E, LaFleur B, Sinari SA, Krueger A, Richie ER, Ehrlich LIR. The initial age-associated decline in early T-cell progenitors reflects fewer pre-thymic progenitors and altered signals in the bone marrow and thymus microenvironments. Aging Cell 2023; 22:e13870. [PMID: 37221658 PMCID: PMC10410006 DOI: 10.1111/acel.13870] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 05/01/2023] [Accepted: 05/03/2023] [Indexed: 05/25/2023] Open
Abstract
Age-related thymus involution results in decreased T-cell production, contributing to increased susceptibility to pathogens and reduced vaccine responsiveness. Elucidating mechanisms underlying thymus involution will inform strategies to restore thymopoiesis with age. The thymus is colonized by circulating bone marrow (BM)-derived thymus seeding progenitors (TSPs) that differentiate into early T-cell progenitors (ETPs). We find that ETP cellularity declines as early as 3 months (3MO) of age in mice. This initial ETP reduction could reflect changes in thymic stromal niches and/or pre-thymic progenitors. Using a multicongenic progenitor transfer approach, we demonstrate that the number of functional TSP/ETP niches does not diminish with age. Instead, the number of pre-thymic lymphoid progenitors in the BM and blood is substantially reduced by 3MO, although their intrinsic ability to seed and differentiate in the thymus is maintained. Additionally, Notch signaling in BM lymphoid progenitors and in ETPs diminishes by 3MO, suggesting reduced niche quality in the BM and thymus contribute to the early decline in ETPs. Together, these findings indicate that diminished BM lymphopoiesis and thymic stromal support contribute to an initial reduction in ETPs in young adulthood, setting the stage for progressive age-associated thymus involution.
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Affiliation(s)
- Jayashree Srinivasan
- Department of Molecular BiosciencesThe University of Texas at AustinAustinTexasUnited States
| | - Anusha Vasudev
- Department of Epigenetics and Molecular CarcinogenesisThe University of Texas MD Anderson Cancer CenterHoustonTexasUnited States
| | - Carolyn Shasha
- Vaccine and Infectious Disease DivisionFred Hutchinson Cancer CenterSeattleWashingtonUnited States
| | - Hilary J. Selden
- Department of Molecular BiosciencesThe University of Texas at AustinAustinTexasUnited States
| | - Encarnacion Perez
- Department of Epigenetics and Molecular CarcinogenesisThe University of Texas MD Anderson Cancer CenterHoustonTexasUnited States
| | - Bonnie LaFleur
- Center for Biomedical Informatics and StatisticsThe University of ArizonaTucsonArizonaUnited States
| | - Shripad A. Sinari
- Center for Biomedical Informatics and StatisticsThe University of ArizonaTucsonArizonaUnited States
| | - Andreas Krueger
- Molecular ImmunologyJustus‐Liebig‐University GiessenGiessenGermany
| | - Ellen R. Richie
- Department of Epigenetics and Molecular CarcinogenesisThe University of Texas MD Anderson Cancer CenterHoustonTexasUnited States
| | - Lauren I. R. Ehrlich
- Department of Molecular BiosciencesThe University of Texas at AustinAustinTexasUnited States
- Department of OncologyLivestrong Cancer Institutes, Dell Medical School at The University of Texas at AustinAustinTexasUnited States
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Alsaab HO. Pathological role of long non-coding (lnc) RNA in the regulation of Wnt/β-catenin signaling pathway during epithelial-mesenchymal transition (EMT). Pathol Res Pract 2023; 248:154566. [PMID: 37285735 DOI: 10.1016/j.prp.2023.154566] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 05/21/2023] [Accepted: 05/23/2023] [Indexed: 06/09/2023]
Abstract
The term "epithelial-mesenchymal transition" (EMT) describes a biological process wherein epithelial cells acquire mesenchymal cell characteristics. This process enables the metastatic cells to migrate and invasion. Recent studies have established the connections between the EMT process and Wnt/β-catenin signaling in cancer. Key cellular functions such as differentiation, proliferation, migration, genetic stability, apoptosis, and stem cell renewal are modulated via Wnt/ β-catenin signaling pathway. Up-regulation of this evolutionarily conserved signal pathway leads to EMT. On the other hand, recent investigations have indicated that non-coding RNAs including microRNAs (miRNAs) and long non-coding RNA (lncRNAs) are involved in regulating of Wnt/β-catenin pathway. A high level of lncRNAs mainly has a positive correlation with EMT. However, lncRNA down-regulation has been observed in promoting EMT. It seems that depending on the specific targets, up-or down-regulation of lncRNAs can stimulate EMT by activating the Wnt/ β-catenin pathway. The evaluation of interactions between lncRNAs and the Wnt/ β-catenin signaling pathway in the regulation of EMT during metastasis can be fascinating. Herein, for the first time, the crucial role of lncRNAs-mediated regulation of the Wnt/ β-catenin signaling pathway in the EMT process of human tumors has been summarized.
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Affiliation(s)
- Hashem O Alsaab
- Pharmaceutics and Pharmaceutical Technology, Taif University, Taif, Saudi Arabia.
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Bastani S, Staal FJT, Canté-Barrett K. The quest for the holy grail: overcoming challenges in expanding human hematopoietic stem cells for clinical use. Stem Cell Investig 2023; 10:15. [PMID: 37457748 PMCID: PMC10345135 DOI: 10.21037/sci-2023-016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023]
Abstract
Hematopoietic stem cell (HSC) transplantation has been the golden standard for many hematological disorders. However, the number of HSCs obtained from several sources, including umbilical cord blood (UCB), often is insufficient for transplantation. For decades, maintaining or even expanding HSCs for therapeutic purposes has been a "holy grail" in stem cell biology. Different methods have been proposed to improve the efficiency of cell expansion and enhance homing potential such as co-culture with stromal cells or treatment with specific agents. Recent progress has shown that this is starting to become feasible using serum-free and well-defined media. Some of these protocols to expand HSCs along with genetic modification have been successfully applied in clinical trials and some others are studied in preclinical and clinical studies. However, the main challenges regarding ex vivo expansion of HSCs such as limited growth potential and tendency to differentiate in culture still need improvements. Understanding the biology of blood stem cells, their niche and signaling pathways has provided possibilities to regulate cell fate decisions and manipulate cells to optimize expansion of HSCs in vitro. Here, we review the plethora of HSC expansion protocols that have been proposed and indicate the current state of the art for their clinical application.
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Affiliation(s)
- Sepideh Bastani
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
| | - Frank J. T. Staal
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
- Department of Pediatrics, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
| | - Kirsten Canté-Barrett
- Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands
- The Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), Leiden University Medical Center, Leiden, The Netherlands
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Bueno MLP, Saad STO, Roversi FM. The antitumor effects of WNT5A against hematological malignancies. J Cell Commun Signal 2023:10.1007/s12079-023-00773-8. [PMID: 37310653 DOI: 10.1007/s12079-023-00773-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 05/30/2023] [Indexed: 06/14/2023] Open
Abstract
The bone marrow (BM) microenvironment (niche) is abnormally altered in acute myeloid leukemia (AML), leading to deficient secretion of proteins, soluble factors, and cytokines by mesenchymal stromal cells (MSC) that modifies the crosstalk between MSC and hematopoietic cells. We focused on a WNT gene/protein family member, WNT5A, which is downregulated in leukemia and correlated with disease progression and poor prognosis. We demonstrated that WNT5A protein upregulated the WNT non-canonical pathway only in leukemic cells, without modulating normal cell behavior. We also introduced a novel WNT5A-mimicking compound, Foxy-5. Our results showed reduction of crucial biological functions that are upregulated in leukemia cells, including ROS generation, cell proliferation, and autophagy, as well as G0/G1 cell cycle arrest. Additionally, Foxy-5 induced early-stage macrophage cell differentiation, a crucial process during leukemia development. At a molecular level, Foxy-5 led to the downregulation of two overexpressed leukemia pathways, PI3K and MAPK, which resulted in a disarrangement of actin polymerization with consequent impairment of CXCL12-induced chemotaxis. Notably, in a novel tri-dimensional bone marrow-mimicking model, Foxy-5 led to reduced leukemia cell growth and similar results were observed in a xenograft in vivo model. Overall, our findings highlight the pivotal role of WNT5A in leukemia and demonstrate that Foxy-5 acts as a specific antineoplastic agent in leukemia, counterbalancing several leukemic oncogenic processes related to the crosstalk in the bone marrow niche, and represents a promising therapeutic option for AML. WNT5A, a WNT gene/protein family member, is naturally secreted by mesenchymal stromal cells and contributes to the maintenance of the bone marrow microenvironment. WNT5A downregulation is correlated with disease progression and poor prognosis. The treatment with Foxy-5, a WNT5A mimetizing compound, counterbalanced several leukemogenic processes that are upregulated in leukemia cells, including ROS generation, cell proliferation, and autophagy and disruption of PI3K and MAPK signaling pathways.
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Affiliation(s)
- Maura Lima Pereira Bueno
- Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro-UNICAMP, Rua Carlos Chagas, 480 - Cidade Universitária Zeferino Vaz - Barão Geraldo, Campinas, São Paulo, 13083-878, Brazil
| | - Sara Teresinha Olalla Saad
- Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro-UNICAMP, Rua Carlos Chagas, 480 - Cidade Universitária Zeferino Vaz - Barão Geraldo, Campinas, São Paulo, 13083-878, Brazil
| | - Fernanda Marconi Roversi
- Hematology and Transfusion Medicine Center - University of Campinas/Hemocentro-UNICAMP, Rua Carlos Chagas, 480 - Cidade Universitária Zeferino Vaz - Barão Geraldo, Campinas, São Paulo, 13083-878, Brazil.
- Department of Surgery Division of Transplantation, Emory University, Atlanta, GA, USA.
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Láinez-González D, Alonso-Aguado AB, Alonso-Dominguez JM. Understanding the Wnt Signaling Pathway in Acute Myeloid Leukemia Stem Cells: A Feasible Key against Relapses. BIOLOGY 2023; 12:biology12050683. [PMID: 37237497 DOI: 10.3390/biology12050683] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Revised: 04/28/2023] [Accepted: 05/03/2023] [Indexed: 05/28/2023]
Abstract
Wnt signaling is a highly conserved pathway in evolution which controls important processes such as cell proliferation, differentiation and migration, both in the embryo and in the adult. Dysregulation of this pathway can favor the development of different types of cancer, such as acute myeloid leukemia and other hematological malignancies. Overactivation of this pathway may promote the transformation of pre-leukemic stem cells into acute myeloid leukemia stem cells, as well as the maintenance of their quiescent state, which confers them with self-renewal and chemoresistance capacity, favoring relapse of the disease. Although this pathway participates in the regulation of normal hematopoiesis, its requirements seem to be greater in the leukemic stem cell population. In this review, we explore the possible therapeutic targeting of Wnt to eradicate the LSCs of AML.
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Affiliation(s)
- Daniel Láinez-González
- Experimental Hematology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain
| | - Ana Belén Alonso-Aguado
- Experimental Hematology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain
| | - Juan Manuel Alonso-Dominguez
- Experimental Hematology, Instituto de Investigación Sanitaria Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Avenida Reyes Católicos 2, 28040 Madrid, Spain
- Hematology Department, Hospital Universitario Fundación Jiménez Díaz, Avenida Reyes Católicos 2, 28040 Madrid, Spain
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Mathur A, Gangwar A, Saluja D. Esculetin releases maturation arrest and induces terminal differentiation in leukemic blast cells by altering the Wnt signaling axes. BMC Cancer 2023; 23:387. [PMID: 37127581 PMCID: PMC10150528 DOI: 10.1186/s12885-023-10818-1] [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: 10/05/2022] [Accepted: 04/06/2023] [Indexed: 05/03/2023] Open
Abstract
BACKGROUND The "Differentiation therapy" has been emerging as a promising and more effective strategy against acute leukemia relapses. OBJECTIVE In extension to the revolutionising therapeutic outcomes of All Trans Retinoic Acid (ATRA) to induce terminal differentiation of Acute Promyelocytic Leukemic (APL) blast cells, we decipher the potential effect of a natural compound "Esculetin" to serve as a differentiating agent in Acute Myeloid Leukemia (AML). Underlaying role of Wnt signaling pathways in esculetin mediated blast cell differentiation was also evaluated. METHODS Human acute myeloid leukemic cells (Kasumi-1) with t(8;21/AML-ETO) translocation were used as a model system. Growth inhibitory and cytotoxic activity of esculetin were analysed using growth kinetics and MTT assay. Morphological alterations, cell scatter characteristics, NBT reduction assay and cell surface marker expression patterns were analysed to detect terminally differentiated phenotypes. We employed RT2profiler PCR array system for the analysis of transcriptome profile of Wnt signaling components. Calcium inhibitors (TMB8 and Amlodipine) and Transforming growth factor beta (TGF-β) were used to modulate the Wnt signaling axes. RESULTS We illustrate cytotoxic as well as blast cell differentiation potential of esculetin on Kasumi-1 cells. Morphological alterations akin to neutrophilic differentiation as well as the corresponding acquisition of myeloid lineage markers indicate terminal differentiation potential of esculetin in leukemic blast cells. Exposure to esculetin also resulted in downregulation of canonical Wnt axis while upto ~ 21 fold upregulation of non-canonical axis associated genes. CONCLUSIONS Our study highlights the importance of selective use of calcium pools as well as "axis shift" of the canonical to non-canonical Wnt signaling upon esculetin treatment which might abrogate the inherent proliferation to release maturation arrest and induce the differentiation in leukemic blast cells. The current findings provide further therapeutic interventions to consider esculetin as a potent differentiating agent to counteract AML relapses.
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Affiliation(s)
- Ankit Mathur
- Delhi School of Public Health, Institution of Eminence, University of Delhi, Delhi, 110007, India
- Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Aman Gangwar
- Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India
| | - Daman Saluja
- Delhi School of Public Health, Institution of Eminence, University of Delhi, Delhi, 110007, India.
- Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, Delhi, 110007, India.
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11
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Panelli P, De Santis E, Colucci M, Tamiro F, Sansico F, Miroballo M, Murgo E, Padovano C, Gusscott S, Ciavarella M, Chavez EA, Bianchi F, Rossi G, Carella AM, Steidl C, Weng AP, Giambra V. Noncanonical β-catenin interactions promote leukemia-initiating activity in early T-cell acute lymphoblastic leukemia. Blood 2023; 141:1597-1609. [PMID: 36315912 PMCID: PMC10651788 DOI: 10.1182/blood.2022017079] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2022] [Revised: 09/13/2022] [Accepted: 09/28/2022] [Indexed: 11/06/2022] Open
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is a T-cell malignancy characterized by cell subsets and enriched with leukemia-initiating cells (LICs). β-Catenin modulates LIC activity in T-ALL. However, its role in maintaining established leukemia stem cells remains largely unknown. To identify functionally relevant protein interactions of β-catenin in T-ALL, we performed coimmunoprecipitation followed by liquid chromatography-mass spectrometry. Here, we report that a noncanonical functional interaction of β-catenin with the Forkhead box O3 (FOXO3) transcription factor positively regulates LIC-related genes, including the cyclin-dependent kinase 4, which is a crucial modulator of cell cycle and tumor maintenance. We also confirm the relevance of these findings using stably integrated fluorescent reporters of β-catenin and FOXO3 activity in patient-derived xenografts, which identify minor subpopulations with enriched LIC activity. In addition, gene expression data at the single-cell level of leukemic cells of primary patients at the time of diagnosis and minimal residual disease (MRD) up to 30 days after the standard treatments reveal that the expression of β-catenin- and FOXO3-dependent genes is present in the CD82+CD117+ cell fraction, which is substantially enriched with LICs in MRD as well as in early T-cell precursor ALL. These findings highlight key functional roles for β-catenin and FOXO3 and suggest novel therapeutic strategies to eradicate aggressive cell subsets in T-ALL.
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Affiliation(s)
- Patrizio Panelli
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Elisabetta De Santis
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Mattia Colucci
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Francesco Tamiro
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Francesca Sansico
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Mattia Miroballo
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Emanuele Murgo
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Costanzo Padovano
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Sam Gusscott
- Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC, Canada
| | - Michele Ciavarella
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | | | - Fabrizio Bianchi
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Giovanni Rossi
- Department of Hematology and Stem Cell Transplant Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Angelo M. Carella
- Department of Hematology and Stem Cell Transplant Unit, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Christian Steidl
- Centre for Lymphoid Cancer, British Columbia Cancer, Vancouver, BC, Canada
| | - Andrew P. Weng
- Terry Fox Laboratory, British Columbia Cancer, Vancouver, BC, Canada
| | - Vincenzo Giambra
- Institute for Stem Cell Biology, Regenerative Medicine and Innovative Therapies, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
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12
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Shen LA, Peng X, Bao Y, Liu C, Zhang H, Li J, Zhu D, Zhang Q. Design, synthesis and biological evaluation of quercetin derivatives as novel β-catenin/B-cell lymphoma 9 protein-protein interaction inhibitors. Eur J Med Chem 2023; 247:115075. [PMID: 36599228 DOI: 10.1016/j.ejmech.2022.115075] [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: 09/17/2022] [Revised: 12/08/2022] [Accepted: 12/29/2022] [Indexed: 01/02/2023]
Abstract
The β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/β-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we first described quercetin and its derivatives had potential inhibitory effects on β-catenin/BCL9 PPI. The most potent compound, quercetin-3'-O-(4-methylpiperazine-1-yl) propyl (C1), directly binded with β-catenin and disrupted the β-catenin/BCL9 interaction in both the protein level and the cellular context. C1 also effectively inhibited colorectal cancer in vitro and showed better selectivity in inhibiting hyperactive Wnt/β-catenin signaling cells like CT26 and HCT116. And we further confirmed that C1 could inhibit CT26 tumor growth in vivo and regulate the tumor immune microenvironment. This study provides a good chemical probe to explore β-catenin-related biology and a drug-like quercetin derivative as novel β-catenin/BCL9 PPI inhibitors for further drug development.
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Affiliation(s)
- Li-An Shen
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Xinyan Peng
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China
| | - Ya Bao
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China
| | - Chenglong Liu
- School of Pharmacy, Fudan University, Shanghai, 201203, China
| | - Hao Zhang
- School of Pharmacy, Fudan University, Shanghai, 201203, China; Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China
| | - Jianqi Li
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China
| | - Di Zhu
- School of Pharmacy, Fudan University, Shanghai, 201203, China; Department of Pharmacology, School of Basic Medical Science, Fudan University, Shanghai, 201100, China.
| | - Qingwei Zhang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China.
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13
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Novel Insights into the Role of Kras in Myeloid Differentiation: Engaging with Wnt/β-Catenin Signaling. Cells 2023; 12:cells12020322. [PMID: 36672256 PMCID: PMC9857056 DOI: 10.3390/cells12020322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 01/07/2023] [Accepted: 01/11/2023] [Indexed: 01/19/2023] Open
Abstract
Cells of the HL-60 myeloid leukemia cell line can be differentiated into neutrophil-like cells by treatment with dimethyl sulfoxide (DMSO). The molecular mechanisms involved in this differentiation process, however, remain unclear. This review focuses on the differentiation of HL-60 cells. Although the Ras proteins, a group of small GTP-binding proteins, are ubiquitously expressed and highly homologous, each has specific molecular functions. Kras was shown to be essential for normal mouse development, whereas Hras and Nras are not. Kras knockout mice develop profound hematopoietic defects, indicating that Kras is required for hematopoiesis in adults. The Wnt/β-catenin signaling pathway plays a crucial role in regulating the homeostasis of hematopoietic cells. The protein β-catenin is a key player in the Wnt/β-catenin signaling pathway. A great deal of evidence shows that the Wnt/β-catenin signaling pathway is deregulated in malignant tumors, including hematological malignancies. Wild-type Kras acts as a tumor suppressor during DMSO-induced differentiation of HL-60 cells. Upon DMSO treatment, Kras translocates to the plasma membrane, and its activity is enhanced. Inhibition of Kras attenuates CD11b expression. DMSO also elevates levels of GSK3β phosphorylation, resulting in the release of unphosphorylated β-catenin from the β-catenin destruction complex and its accumulation in the cytoplasm. The accumulated β-catenin subsequently translocates into the nucleus. Inhibition of Kras attenuates Lef/Tcf-sensitive transcription activity. Thus, upon treatment of HL-60 cells with DMSO, wild-type Kras reacts with the Wnt/β-catenin pathway, thereby regulating the granulocytic differentiation of HL-60 cells. Wild-type Kras and the Wnt/β-catenin signaling pathway are activated sequentially, increasing the levels of expression of C/EBPα, C/EBPε, and granulocyte colony-stimulating factor (G-CSF) receptor.
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14
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Inhibition of beta-catenin shows therapeutic potential in head and neck squamous cell carcinoma in vitro. Eur Arch Otorhinolaryngol 2023; 280:399-408. [PMID: 36001136 PMCID: PMC9813240 DOI: 10.1007/s00405-022-07598-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Accepted: 08/04/2022] [Indexed: 01/09/2023]
Abstract
Beta-catenin is known to be a vital component of the canonical Wnt signaling cascade, involved in the carcinogenesis of different solid tumors. We aimed to evaluate the effects of Beta-catenin inhibition in head and neck squamous cell carcinoma (HNSCC) in vitro. The small molecular compound MSAB was used to inhibit Wnt/Beta-catenin signaling in a human papillomavirus (HPV)-positive and HPV-negative cell line and its effects on cell proliferation, migration, colony formation, apoptosis, as well as radiosensitizing properties were assessed. Significant antineoplastic effects were observed in both cell lines. Interestingly, stronger anti-neoplastic and radiosensitizing effects were observed in the HPV-negative cell line, whereas stronger anti-migratory potential was detected in HPV-positive HNSCC cells. In conclusion, our findings suggest MSAB as a potential therapeutic agent for HNSCC. Further studies are warranted to unravel the mechanistic background of our findings.
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15
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Maier T, Stoiber S, Gurnhofer E, Haas M, Kenner L, Heiduschka G, Kadletz-Wanke L, Brkic FF. Inhibition of beta-catenin shows therapeutic potential in head and neck squamous cell carcinoma in vitro. Eur Arch Otorhinolaryngol 2023. [PMID: 36001136 DOI: 10.1007/s00405-022-07598-y/figures/4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023]
Abstract
Beta-catenin is known to be a vital component of the canonical Wnt signaling cascade, involved in the carcinogenesis of different solid tumors. We aimed to evaluate the effects of Beta-catenin inhibition in head and neck squamous cell carcinoma (HNSCC) in vitro. The small molecular compound MSAB was used to inhibit Wnt/Beta-catenin signaling in a human papillomavirus (HPV)-positive and HPV-negative cell line and its effects on cell proliferation, migration, colony formation, apoptosis, as well as radiosensitizing properties were assessed. Significant antineoplastic effects were observed in both cell lines. Interestingly, stronger anti-neoplastic and radiosensitizing effects were observed in the HPV-negative cell line, whereas stronger anti-migratory potential was detected in HPV-positive HNSCC cells. In conclusion, our findings suggest MSAB as a potential therapeutic agent for HNSCC. Further studies are warranted to unravel the mechanistic background of our findings.
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Affiliation(s)
- Tobias Maier
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Stefan Stoiber
- Department of Pathology, Medical University of Vienna, Vienna, Austria
- Christian Doppler Laboratory for Applied Metabolomics, Vienna, Austria
| | | | - Markus Haas
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Lukas Kenner
- Department of Pathology, Medical University of Vienna, Vienna, Austria.
- Christian Doppler Laboratory for Applied Metabolomics, Vienna, Austria.
- Unit of Laboratory Animal Pathology, University of Veterinary Medicine, Vienna, Austria.
- CBmed GmbH-Center for Biomarker Research in Medicine, Graz, Austria.
| | - Gregor Heiduschka
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Lorenz Kadletz-Wanke
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
| | - Faris F Brkic
- Department of Otorhinolaryngology and Head and Neck Surgery, Medical University of Vienna, Vienna, Austria
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16
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Harrison KS, Jones C. Regulation of herpes simplex virus type 1 latency-reactivation cycle and ocular disease by cellular signaling pathways. Exp Eye Res 2022; 218:109017. [PMID: 35240194 PMCID: PMC9191828 DOI: 10.1016/j.exer.2022.109017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/18/2022] [Accepted: 02/23/2022] [Indexed: 11/04/2022]
Abstract
Following acute infection, herpes simplex virus type 1 (HSV-1) establishes life-long latency in sensory and other neurons. Recurrent ocular HSV-1 outbreaks are generally due to reactivation from latency. The HSV-1 latency-reactivation cycle is a complex virus-host relationship. The viral encoded latency-associated transcript (LAT) is abundantly expressed in latency and encodes several micro-RNAs and other small non-coding RNAs, which may regulate expression of key viral and cellular genes. Certain cellular signaling pathways, including Wnt/β-catenin and mTOR pathway, mediate certain aspect of the latency-reactivation cycle. Stress, via activation of the glucocorticoid receptor and other stress induced cellular transcription factors, are predicted to trigger reactivation from latency by stimulating viral gene expression and impairing immune responses and inflammation. These observations suggest stress and certain cellular signaling pathways play key roles in regulating the latency-reactivation cycle and recurrent ocular disease.
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Affiliation(s)
- Kelly S Harrison
- Oklahoma State University, College of Veterinary Medicine, Department of Veterinary Pathobiology, Rm 250 McElroy Hall, Stillwater, OK, 74078, USA.
| | - Clinton Jones
- Oklahoma State University, College of Veterinary Medicine, Department of Veterinary Pathobiology, Rm 250 McElroy Hall, Stillwater, OK, 74078, USA.
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17
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Abou-Fadel J, Bhalli M, Grajeda B, Zhang J. CmP Signaling Network Leads to Identification of Prognostic Biomarkers for Triple-Negative Breast Cancer in Caucasian Women. Genet Test Mol Biomarkers 2022; 26:198-219. [PMID: 35481969 DOI: 10.1089/gtmb.2021.0221] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective: Triple-negative breast cancer (TNBC) constitutes ∼15% of all diagnosed invasive breast cancer cases with limited options for treatment since immunotherapies that target ER, PR, and HER2 receptors are ineffective. Progesterone (PRG) can induce its effects through either classic, nonclassic, or combined responses by binding to classic nuclear PRG receptors (nPRs) or nonclassic membrane PRG receptors (mPRs). Under PRG-induced actions, we previously demonstrated that the CCM signaling complex (CSC) can couple both nPRs and mPRs into a CmPn signaling network, which plays an important role during nPR(+) breast cancer tumorigenesis. We recently defined the novel CmP signaling network in African American women (AAW)-derived TNBC cells, which overlapped with our previously defined CmPn network in nPR(+) breast cancer cells. Methods: Under mPR-specific steroid actions, we measured alterations to key tumorigenic pathways in Caucasian American women (CAW)- derived TNBC cells, with RNAseq/proteomic and systems biology approaches. Exemption from ethics approval from IRB: This study only utilized cultured NBC cell lines with publicly available TNBC clinical data sets. Results: Our results demonstrated that TNBCs in CAW share similar altered signaling pathways, as TNBCs in AAW, under mPR-specific steroid actions, demonstrating the overall aggressive nature of TNBCs, regardless of racial differences. Furthermore, in this report, we have deconvoluted the CmP signalosome, using systems biology approaches and CAW-TNBC clinical data, to identify 21 new CAW-TNBC-specific prognostic biomarkers that reinforce the definitive role of CSC and mPR signaling during CAW-TNBC tumorigenesis. Conclusion: This new set of potential prognostic biomarkers may revolutionize molecular mechanisms and currently known concepts of tumorigenesis in CAW-TNBCs, leading to hopeful new therapeutic strategies.
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Affiliation(s)
- Johnathan Abou-Fadel
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, Texas, USA
| | - Muaz Bhalli
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, Texas, USA
| | - Brian Grajeda
- Department of Biological Sciences, University of Texas at El Paso, El Paso, Texas, USA
| | - Jun Zhang
- Department of Molecular and Translational Medicine (MTM), Texas Tech University Health Science Center El Paso, El Paso, Texas, USA
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18
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Tanton H, Sewastianik T, Seo HS, Remillard D, Pierre RS, Bala P, Aitymbayev D, Dennis P, Adler K, Geffken E, Yeoh Z, Vangos N, Garbicz F, Scott D, Sethi N, Bradner J, Dhe-Paganon S, Carrasco RD. A novel β-catenin/BCL9 complex inhibitor blocks oncogenic Wnt signaling and disrupts cholesterol homeostasis in colorectal cancer. SCIENCE ADVANCES 2022; 8:eabm3108. [PMID: 35486727 PMCID: PMC9054024 DOI: 10.1126/sciadv.abm3108] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 03/16/2022] [Indexed: 06/14/2023]
Abstract
Dysregulated Wnt/β-catenin signaling is implicated in the pathogenesis of many human cancers, including colorectal cancer (CRC), making it an attractive clinical target. With the aim of inhibiting oncogenic Wnt activity, we developed a high-throughput screening AlphaScreen assay to identify selective small-molecule inhibitors of the interaction between β-catenin and its coactivator BCL9. We identified a compound that consistently bound to β-catenin and specifically inhibited in vivo native β-catenin/BCL9 complex formation in CRC cell lines. This compound inhibited Wnt activity, down-regulated expression of the Wnt/β-catenin signature in gene expression studies, disrupted cholesterol homeostasis, and significantly reduced the proliferation of CRC cell lines and tumor growth in a xenograft mouse model of CRC. This study has therefore identified a specific small-molecule inhibitor of oncogenic Wnt signaling, which may have value as a probe for functional studies and has important implications for the development of novel therapies in patients with CRC.
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Affiliation(s)
- Helen Tanton
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Tomasz Sewastianik
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine,, Warsaw, Poland
| | - Hyuk-Soo Seo
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - David Remillard
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Roodolph St. Pierre
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Pratyusha Bala
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
| | - Daulet Aitymbayev
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
| | - Peter Dennis
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Keith Adler
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Ezekiel Geffken
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Zoe Yeoh
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Nicholas Vangos
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Filip Garbicz
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine,, Warsaw, Poland
| | - David Scott
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Nilay Sethi
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA, USA
- Gastrointestinal Cancer Center, Dana-Farber Cancer Institute, Boston, MA, USA
- Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
| | - James Bradner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Sirano Dhe-Paganon
- Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA, USA
| | - Ruben D. Carrasco
- Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA
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19
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Targeting β-catenin in acute myeloid leukaemia: past, present, and future perspectives. Biosci Rep 2022; 42:231097. [PMID: 35352805 PMCID: PMC9069440 DOI: 10.1042/bsr20211841] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2022] [Revised: 03/14/2022] [Accepted: 03/30/2022] [Indexed: 11/24/2022] Open
Abstract
Acute myeloid leukaemia (AML) is an aggressive disease of the bone marrow with a poor prognosis. Evidence suggests long established chemotherapeutic regimens used to treat AML are reaching the limits of their efficacy, necessitating the urgent development of novel targeted therapies. Canonical Wnt signalling is an evolutionary conserved cascade heavily implicated in normal developmental and disease processes in humans. For over 15 years its been known that the central mediator of this pathway, β-catenin, is dysregulated in AML promoting the emergence, maintenance, and drug resistance of leukaemia stem cells. Yet, despite this knowledge, and subsequent studies demonstrating the therapeutic potential of targeting Wnt activity in haematological cancers, β-catenin inhibitors have not yet reached the clinic. The aim of this review is to summarise the current understanding regarding the role and mechanistic dysregulation of β-catenin in AML, and assess the therapeutic merit of pharmacologically targeting this molecule, drawing on lessons from other disease contexts.
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20
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Bouali S, Hétu-Arbour R, Gardet C, Heinonen KM. Vangl2 Promotes Hematopoietic Stem Cell Expansion. Front Cell Dev Biol 2022; 10:760248. [PMID: 35399538 PMCID: PMC8987925 DOI: 10.3389/fcell.2022.760248] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 02/28/2022] [Indexed: 11/21/2022] Open
Abstract
Regulation of hematopoietic stem cell (HSC) self-renewal and differentiation is essential for their maintenance, and HSC polarity has been shown to play an important role in this regulation. Vangl2, a key component of the Wnt/polarity pathway, is expressed by fetal and adult HSCs, but its role in hematopoiesis and HSC function is unknown. Here we show the deletion of Vangl2 in mouse hematopoietic cells impairs HSC expansion and hematopoietic recovery post-transplant. Old Vangl2-deficient mice showed increased expansion of myeloid-biased multipotent progenitor cells concomitant with splenomegaly. Moreover, Vangl2-deficient cells were not able to effectively reconstitute the recipient bone marrow in serial transplants, or when coming from slightly older donors, demonstrating impaired self-renewal or expansion. Aged Vangl2-deficient HSCs displayed increased levels of cell cycle inhibitor p16INK4a and active β–catenin, which could contribute to their impaired function. Overall, our findings identify Vangl2 as a new regulator of hematopoiesis.
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Affiliation(s)
- Sarah Bouali
- Institut National de La Recherche Scientifique, INRS-Centre Armand-Frappier Santé Biotechnologie, Université du Québec, Laval, QC, Canada
| | - Roxann Hétu-Arbour
- Institut National de La Recherche Scientifique, INRS-Centre Armand-Frappier Santé Biotechnologie, Université du Québec, Laval, QC, Canada
| | - Célia Gardet
- Institut National de La Recherche Scientifique, INRS-Centre Armand-Frappier Santé Biotechnologie, Université du Québec, Laval, QC, Canada
- Institut des Sciences et Industries du Vivant et de l’Environnement - AgroParisTech, Université Paris-Saclay, Paris, France
| | - Krista M. Heinonen
- Institut National de La Recherche Scientifique, INRS-Centre Armand-Frappier Santé Biotechnologie, Université du Québec, Laval, QC, Canada
- *Correspondence: Krista M. Heinonen,
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21
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Combination of Histone Deacetylase Inhibitor Panobinostat (LBH589) with β-Catenin Inhibitor Tegavivint (BC2059) Exerts Significant Anti-Myeloma Activity Both In Vitro and In Vivo. Cancers (Basel) 2022; 14:cancers14030840. [PMID: 35159107 PMCID: PMC8834319 DOI: 10.3390/cancers14030840] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 01/31/2022] [Accepted: 02/04/2022] [Indexed: 02/06/2023] Open
Abstract
Over the last three decades changes in the treatment paradigm for newly diagnosed multiple myeloma (MM) have led to a significant increase in overall survival. Despite this, the majority of patients relapse after one or more lines of treatment while acquiring resistance to available therapies. Panobinostat, a pan-histone deacetylase inhibitor, was approved by the FDA in 2015 for patients with relapsed MM but how to incorporate panobinostat most effectively into everyday practice remains unclear. Dysregulation of the Wnt canonical pathway, and its key mediator β-catenin, has been shown to be important for the evolution of MM and the acquisition of drug resistance, making it a potentially attractive therapeutic target. Despite concerns regarding the safety of Wnt pathway inhibitors, we have recently shown that the β-catenin inhibitor Tegavivint is deliverable and effective in in vivo models of MM. In this study we show that the combination of low concentrations of panobinostat and Tegavivint have significant in vitro and in vivo anti-MM effects including in the context of proteasome inhibitor resistance, by targeting both aerobic glycolysis and mitochondrial respiration and the down-regulation of down-stream β-catenin targets including myc, cyclinD1, and cyclinD2. The significant anti-MM effect of this novel combination warrants further evaluation for the treatment of MM patients with relapsed and/or refractory MM.
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22
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Pepe F, Bill M, Papaioannou D, Karunasiri M, Walker A, Naumann E, Snyder K, Ranganathan P, Dorrance A, Garzon R. Targeting Wnt signaling in acute myeloid leukemia stem cells. Haematologica 2022; 107:307-311. [PMID: 34525792 PMCID: PMC8719090 DOI: 10.3324/haematol.2020.266155] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Accepted: 09/08/2021] [Indexed: 11/17/2022] Open
Affiliation(s)
- Felice Pepe
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Marius Bill
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | | | | | - Allison Walker
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Eric Naumann
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Katiri Snyder
- The Ohio State University Comprehensive Cancer Center, Columbus, OH
| | - Parvathi Ranganathan
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
| | - Adrienne Dorrance
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH
| | - Ramiro Garzon
- The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA; Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH.
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23
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Reister S, Mahotka C, Grinstein E. Nucleolin as activator of TCF7L2 in human hematopoietic stem/progenitor cells. Leukemia 2021; 35:3616-3618. [PMID: 34799688 PMCID: PMC8632675 DOI: 10.1038/s41375-021-01434-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/10/2021] [Accepted: 09/17/2021] [Indexed: 11/08/2022]
Affiliation(s)
- Sven Reister
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Csaba Mahotka
- Institute of Pathology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
| | - Edgar Grinstein
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
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24
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Lee JW, Lee HY. Targeting Cancer Stem Cell Markers or Pathways: A Potential Therapeutic Strategy for Oral Cancer Treatment. Int J Stem Cells 2021; 14:386-399. [PMID: 34711702 PMCID: PMC8611309 DOI: 10.15283/ijsc21084] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/14/2021] [Accepted: 06/05/2021] [Indexed: 12/16/2022] Open
Abstract
Cancer stem cells (CSCs) are a small subset of cancer cells with stem cell-like properties, self-renewal potential, and differentiation capacity into multiple cell types. Critical genetic alterations or aberrantly activated signaling pathways associated with drug resistance and recurrence have been observed in multiple types of CSCs. In this context, CSCs are considered to be responsible for tumor initiation, growth, progression, therapeutic resistance, and metastasis. Therefore, to effectively eradicate CSCs, tremendous efforts have been devoted to identify specific target molecules that play a critical role in regulating their distinct functions and to develop novel therapeutics, such as proteins, monoclonal antibodies, selective small molecule inhibitors, and small antisense RNA (asRNA) drugs. Similar to other CSC types, oral CSCs can be characterized by certain pluripotency-associated markers, and oral CSCs can also survive and form 3D tumor spheres in suspension culture conditions. These oral CSC-targeting therapeutics selectively suppress specific surface markers or key signaling components and subsequently inhibit the stem-like properties of oral CSCs. A large number of new therapeutic candidates have been tested, and some products are currently in the pre-clinical or clinical development phase. In the present study, we review new oral CSC-targeted therapeutic strategies and discuss the various specific CSC surface markers and key signaling components involved in the stem-like properties, growth, drug resistance, and tumorigenicity of oral CSCs.
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Affiliation(s)
- Jin Woo Lee
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon, Korea.,Department of Molecular Medicine, School of Medicine, Gachon University, Incheon, Korea
| | - Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, Goesan, Korea.,Division of Science Education, Kangwon National University, Chuncheon, Korea
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25
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Sharma A, Mir R, Galande S. Epigenetic Regulation of the Wnt/β-Catenin Signaling Pathway in Cancer. Front Genet 2021; 12:681053. [PMID: 34552611 PMCID: PMC8450413 DOI: 10.3389/fgene.2021.681053] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Studies over the past four decades have elucidated the role of Wnt/β-catenin mediated regulation in cell proliferation, differentiation and migration. These processes are fundamental to embryonic development, regeneration potential of tissues, as well as cancer initiation and progression. In this review, we focus on the epigenetic players which influence the Wnt/β-catenin pathway via modulation of its components and coordinated regulation of the Wnt target genes. The role played by crosstalk with other signaling pathways mediating tumorigenesis is also elaborated. The Hippo/YAP pathway is particularly emphasized due to its extensive crosstalk via the Wnt destruction complex. Further, we highlight the recent advances in developing potential therapeutic interventions targeting the epigenetic machinery based on the characterization of these regulatory networks for effective treatment of various cancers and also for regenerative therapies.
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Affiliation(s)
- Ankita Sharma
- Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune, India
| | - Rafeeq Mir
- Centre for Interdisciplinary Research and Innovations, University of Kashmir, Srinagar, India
| | - Sanjeev Galande
- Centre of Excellence in Epigenetics, Department of Biology, Indian Institute of Science Education and Research, Pune, India.,Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Greater Noida, India
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26
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Hiremath IS, Goel A, Warrier S, Kumar AP, Sethi G, Garg M. The multidimensional role of the Wnt/β-catenin signaling pathway in human malignancies. J Cell Physiol 2021; 237:199-238. [PMID: 34431086 DOI: 10.1002/jcp.30561] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 07/28/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023]
Abstract
Several signaling pathways have been identified as important for developmental processes. One of such important cascades is the Wnt/β-catenin signaling pathway, which can regulate various physiological processes such as embryonic development, tissue homeostasis, and tissue regeneration; while its dysregulation is implicated in several pathological conditions especially cancers. Interestingly, deregulation of the Wnt/β-catenin pathway has been reported to be closely associated with initiation, progression, metastasis, maintenance of cancer stem cells, and drug resistance in human malignancies. Moreover, several genetic and experimental models support the inhibition of the Wnt/β-catenin pathway to answer the key issues related to cancer development. The present review focuses on different regulators of Wnt pathway and how distinct mutations, deletion, and amplification in these regulators could possibly play an essential role in the development of several cancers such as colorectal, melanoma, breast, lung, and leukemia. Additionally, we also provide insights on diverse classes of inhibitors of the Wnt/β-catenin pathway, which are currently in preclinical and clinical trial against different cancers.
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Affiliation(s)
- Ishita S Hiremath
- Department of Bioengineering, Birla Institute of Technology, Mesra, Ranchi, Jharkhand, India
| | - Arul Goel
- La Canada High School, La Canada Flintridge, California, USA
| | - Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India.,Cuor Stem Cellutions Pvt Ltd, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, Karnataka, India
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Cancer Science Institute of Singapore and Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Manoj Garg
- Amity Institute of Biotechnology, Amity University, Manesar, Haryana, India
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27
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Maurya S, Yang W, Tamai M, Zhang Q, Erdmann-Gilmore P, Bystry A, Martins Rodrigues F, Valentine MC, Wong WH, Townsend R, Druley TE. Loss of KMT2C reprograms the epigenomic landscape in hPSCs resulting in NODAL overexpression and a failure of hemogenic endothelium specification. Epigenetics 2021; 17:220-238. [PMID: 34304711 PMCID: PMC8865227 DOI: 10.1080/15592294.2021.1954780] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Germline or somatic variation in the family of KMT2 lysine methyltransferases have been associated with a variety of congenital disorders and cancers. Notably, KMT2A-fusions are prevalent in 70% of infant leukaemias but fail to phenocopy short latency leukaemogenesis in mammalian models, suggesting additional factors are necessary for transformation. Given the lack of additional somatic mutation, the role of epigenetic regulation in cell specification, and our prior results of germline KMT2C variation in infant leukaemia patients, we hypothesized that germline dysfunction of KMT2C altered haematopoietic specification. In isogenic KMT2C KO hPSCs, we found genome-wide differences in histone modifications at active and poised enhancers, leading to gene expression profiles akin to mesendoderm rather than mesoderm highlighted by a significant increase in NODAL expression and WNT inhibition, ultimately resulting in a lack of in vitro hemogenic endothelium specification. These unbiased multi-omic results provide new evidence for germline mechanisms increasing risk of early leukaemogenesis.
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Affiliation(s)
- Shailendra Maurya
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
| | - Wei Yang
- McDonnell Genome Institute, Genome Technology Access Center, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
| | - Minori Tamai
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
| | - Qiang Zhang
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Petra Erdmann-Gilmore
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Amelia Bystry
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
| | | | - Mark C Valentine
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
| | - Wing H Wong
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
| | - Reid Townsend
- Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Todd E Druley
- Department of Pediatrics, Division of Pediatric Hematology and Oncology, Washington University in St Louis School of Medicine, St. Louis, Missouri, United States
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28
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Hassan SS, Maqsood N, Wang Q, Tao S, Sadaf S. A panel of epigenetically dysregulated Wnt signaling pathway genes for non-invasive diagnosis of pediatric acute lymphoblastic leukemia. Cancer Biomark 2021; 32:459-470. [PMID: 34334378 DOI: 10.3233/cbm-200814] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Genetic and epigenetic dysregulation of Wnt signaling pathway is widely linked up with abnormal proliferation and/or epithelial-to-mesenchymal transition, in different cancer cell types. OBJECTIVE In the present research, we have tested whether promoter DNA methylation of a set of Wnt/non-Wnt genes such as [cadherin-2 (CDH2)], "present in circulation", could serve as "bone-marrow biopsy surrogate" and help in diagnosing the status, sub-type or treatment outcome in pediatric acute lymphoblastic leukemia (ALL) patients. METHODS Promoter DNA methylation was quantified in the bisulfite modified blood from the pediatric ALL patients (n= 86) in comparison with age-matched cancer-free subjects (n= 28), using real-time methylation specific PCR followed by rigorous statistical validations. RESULTS The observed methylation index, sensitivity and specificity of selected molecular markers (viz., SALL1, WNT5α, LRP1b, CDH2) in patients' liquid-biopsies was clinically significant showing high positive correlation in the pre-B ALL cases (p-value < 0.001). A substantial drop in promoter methylation signal of the follow-up/post-treatment patients was also noted (p-value < 0.001), which suggested an impending role of minimally invasive liquid-biopsy approach in the diagnosis and/or therapeutic monitoring of pediatric leukemia. CONCLUSIONS Whilst the reported metadata provides useful insight into the plausible involvement of epigenetic glitches in leukemogensis, our findings strengthen the remarkable functional consequences of dysregulated Wnt signaling genes in the hematological malignancies besides offering a novel panel of epigenetic marks.
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Affiliation(s)
- Syeda Saliha Hassan
- Biopharmaceuticals and Biomarkers Discovery Lab., Institute of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan
| | - Neha Maqsood
- Biopharmaceuticals and Biomarkers Discovery Lab., Institute of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan
| | - Qingbing Wang
- Department of Interventional Radiology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sun Tao
- Key Laboratory of Smart Drug Delivery (Ministry of Education), State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Department of Pharmaceutics, School of Pharmacy, Research Center on Aging and Medicine, Fudan University, Shanghai, China
| | - Saima Sadaf
- Biopharmaceuticals and Biomarkers Discovery Lab., Institute of Biochemistry and Biotechnology, University of the Punjab, Lahore, Pakistan
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29
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Martelli AM, Evangelisti C, Paganelli F, Chiarini F, McCubrey JA. GSK-3: a multifaceted player in acute leukemias. Leukemia 2021; 35:1829-1842. [PMID: 33811246 DOI: 10.1038/s41375-021-01243-z] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 03/22/2021] [Accepted: 03/23/2021] [Indexed: 02/06/2023]
Abstract
Glycogen synthase kinase 3 (GSK-3) consists of two isoforms (α and β) that were originally linked to glucose metabolism regulation. However, GSK-3 is also involved in several signaling pathways controlling many different key functions in healthy cells. GSK-3 is a unique kinase in that its isoforms are constitutively active, while they are inactivated mainly through phosphorylation at Ser residues by a variety of upstream kinases. In the early 1990s, GSK-3 emerged as a key player in cancer cell pathophysiology. Since active GSK-3 promotes destruction of multiple oncogenic proteins (e.g., β-catenin, c-Myc, Mcl-1) it was considered to be a tumor suppressor. Accordingly, GSK-3 is frequently inactivated in human cancer via aberrant regulation of upstream signaling pathways. More recently, however, it has emerged that GSK-3 isoforms display also oncogenic properties, as they up-regulate pathways critical for neoplastic cell proliferation, survival, and drug-resistance. The regulatory roles of GSK-3 isoforms in cell cycle, apoptosis, DNA repair, tumor metabolism, invasion, and metastasis reflect the therapeutic relevance of these kinases and provide the rationale for combining GSK-3 inhibitors with other targeted drugs. Here, we discuss the multiple and often conflicting roles of GSK-3 isoforms in acute leukemias. We also review the current status of GSK-3 inhibitor development for innovative leukemia therapy.
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Affiliation(s)
- Alberto M Martelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Camilla Evangelisti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Francesca Paganelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.,CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza" Unit of Bologna, Bologna, Italy.,IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - Francesca Chiarini
- CNR Institute of Molecular Genetics "Luigi Luca Cavalli-Sforza" Unit of Bologna, Bologna, Italy.,IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - James A McCubrey
- Department of Microbiology & Immunology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
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30
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Jiang D, He Y, Mo Q, Liu E, Li X, Huang L, Zhang Q, Chen F, Li Y, Shao H. PRICKLE1, a Wnt/PCP signaling component, is overexpressed and associated with inferior prognosis in acute myeloid leukemia. J Transl Med 2021; 19:211. [PMID: 34001134 PMCID: PMC8130533 DOI: 10.1186/s12967-021-02873-8] [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: 02/11/2021] [Accepted: 05/03/2021] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND Prickle planar cell polarity protein 1 (PRICKLE1), a core component of the non-canonical Wnt/planar cell polarity (PCP) pathway, was recently reported to be upregulated and correlated with poor prognosis in solid cancers. However, the effect of PRICKLE1 on acute myeloid leukemia (AML) remains unknown. This study aims to characterize the prognostic significance of PRICKLE1 expression in patients with AML. METHODS RNA-seq was performed to compare mRNA expression profiles of AML patients and healthy controls. qRT-PCR and western blotting were used to analyze the expression of PRICKLE1 in AML patients and cell lines, and two independent datasets (TCGA-LAML and TARGET-AML) online were used to validate the expression results. The correlations between the expression of PRICKLE1 and clinical features were further analyzed. RESULTS Our data showed that PRICKLE1 expression levels were markedly high in AML patients at the time of diagnosis, decreased after complete remission and increased again at relapse. Of note, PRICKLE1 was highly expressed in drug resistant AML cells and monocytic-AML patients. High PRICKLE1 expression was found in FLT3/DNMT3A/IDH1/IDH2-mutant AML and associated with poor prognosis. Furthermore, high expression of PRICKLE1 may be correlated with migration and invasion components upregulation in AML patients. CONCLUSIONS These results indicated that high PRICKLE1 expression may be a poor prognostic biomarker and therapeutic target of AML.
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Affiliation(s)
- Duanfeng Jiang
- Department of Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yanjuan He
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qiuyu Mo
- Department of Hematology, Affiliated Hospital of Guilin Medical University, Guilin, Guangxi, China
| | - Enyi Liu
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Xin Li
- Department of Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Lihua Huang
- Center for Medical Experiments, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Qin Zhang
- Department of Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Fangping Chen
- Department of Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yan Li
- Department of Hematology, Xiangya Hospital, Central South University, Changsha, Hunan, China.
| | - Haigang Shao
- Department of Hematology, The 3rd Xiangya Hospital, Central South University, Changsha, Hunan, China.
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31
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Ferrara B, Belbekhouche S, Habert D, Houppe C, Vallée B, Bourgoin-Voillard S, Cohen JL, Cascone I, Courty J. Cell surface nucleolin as active bait for nanomedicine in cancer therapy: a promising option. NANOTECHNOLOGY 2021; 32:322001. [PMID: 33892482 DOI: 10.1088/1361-6528/abfb30] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 04/23/2021] [Indexed: 06/12/2023]
Abstract
Conventional chemotherapy used against cancer is mostly limited due to their non-targeted nature, affecting normal tissue and causing undesirable toxic effects to the affected tissue. With the aim of improving these treatments both therapeutically and in terms of their safety, numerous studies are currently being carried out using nanoparticles (NPs) as a vector combining tumor targeting and carrying therapeutic tools. In this context, it appears that nucleolin, a molecule over-expressed on the surface of tumor cells, is an interesting therapeutic target. Several ligands, antagonists of nucleolin of various origins, such as AS1411, the F3 peptide and the multivalent pseudopeptide N6L have been developed and studied as therapeutic tools against cancer. Over the last ten years or so, numerous studies have been published demonstrating that these antagonists can be used as tumor targeting agents with NPs from various origins. Focusing on nucleolin ligands, the aim of this article is to review the literature recently published or under experimentation in our research team to evaluate the efficacy and future development of these tools as anti-tumor agents.
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Affiliation(s)
- Benedetta Ferrara
- Université Paris-Est Creteil, Immunorégulation et Biothérapie, INSERM U955, Hôpital Henri Mondor, F-94010 Créteil, France
| | - Sabrina Belbekhouche
- Université Paris-Est Creteil, CNRS, Institut Chimie et Matériaux Paris Est, UMR 7182, 2 Rue Henri Dunant, F-94320 Thiais, France
| | - Damien Habert
- Université Paris-Est Creteil, Immunorégulation et Biothérapie, INSERM U955, Hôpital Henri Mondor, F-94010 Créteil, France
| | - Claire Houppe
- Université Paris-Est Creteil, Immunorégulation et Biothérapie, INSERM U955, Hôpital Henri Mondor, F-94010 Créteil, France
| | - Benoit Vallée
- Université Paris-Est Creteil, Immunorégulation et Biothérapie, INSERM U955, Hôpital Henri Mondor, F-94010 Créteil, France
| | - Sandrine Bourgoin-Voillard
- Université Paris-Est Creteil, Immunorégulation et Biothérapie, INSERM U955, Hôpital Henri Mondor, F-94010 Créteil, France
- Université Grenoble Alpes, Laboratory of Fundamental and Applied Bioenergetics/Prométhée Proteomic Platform, UGA-INSERM U1055-CHUGA, Grenoble, France
- Université Grenoble Alpes, CNRS, Grenoble INP, CHU Grenoble Alpes, TIMC, PROMETHEE Proteomic Platform, Grenoble, France
| | - José L Cohen
- Université Paris-Est Creteil, Immunorégulation et Biothérapie, INSERM U955, Hôpital Henri Mondor, F-94010 Créteil, France
| | - Ilaria Cascone
- Université Paris-Est Creteil, Immunorégulation et Biothérapie, INSERM U955, Hôpital Henri Mondor, F-94010 Créteil, France
| | - José Courty
- Université Paris-Est Creteil, Immunorégulation et Biothérapie, INSERM U955, Hôpital Henri Mondor, F-94010 Créteil, France
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32
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Chiara VD, Daxinger L, Staal FJT. The Route of Early T Cell Development: Crosstalk between Epigenetic and Transcription Factors. Cells 2021; 10:1074. [PMID: 33946533 PMCID: PMC8147249 DOI: 10.3390/cells10051074] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/25/2021] [Accepted: 04/26/2021] [Indexed: 12/21/2022] Open
Abstract
Hematopoietic multipotent progenitors seed the thymus and then follow consecutive developmental stages until the formation of mature T cells. During this process, phenotypic changes of T cells entail stage-specific transcriptional programs that underlie the dynamic progression towards mature lymphocytes. Lineage-specific transcription factors are key drivers of T cell specification and act in conjunction with epigenetic regulators that have also been elucidated as crucial players in the establishment of regulatory networks necessary for proper T cell development. In this review, we summarize the activity of transcription factors and epigenetic regulators that together orchestrate the intricacies of early T cell development with a focus on regulation of T cell lineage commitment.
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Affiliation(s)
- Veronica Della Chiara
- Department of Human Genetics, Leiden University Medical Centre (LUMC), 2300 RC Leiden, The Netherlands; (V.D.C.); (L.D.)
| | - Lucia Daxinger
- Department of Human Genetics, Leiden University Medical Centre (LUMC), 2300 RC Leiden, The Netherlands; (V.D.C.); (L.D.)
| | - Frank J. T. Staal
- Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
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33
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Abstract
Wnt/β-catenin signaling is crucial both in normal embryonic development and throughout the life of an organism. Moreover, aberrant Wnt signaling has been associated with various diseases, especially cancer and fibrosis. Recent research suggests that direct targeting of the β-catenin/BCL9 protein-protein interaction (PPI) is a promising strategy to block the Wnt pathway. Progress in understanding the cocrystalline complex and mechanism of action of the β-catenin/BCL9 interaction facilitates the discovery process of its inhibitors, but only a few inhibitors have been reported. In this review, the discovery and development of β-catenin/BCL9 PPI inhibitors in the areas of drug design, structure-activity relationships and biological and biochemical properties are summarized. In addition, perspectives for the future development of β-catenin/BCL9 PPI inhibitors are explored.
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34
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Cassaro A, Grillo G, Notaro M, Gliozzo J, Esposito I, Reda G, Trojani A, Valentini G, Di Camillo B, Cairoli R, Beghini A. FZD6 triggers Wnt-signalling driven by WNT10B IVS1 expression and highlights new targets in T-cell acute lymphoblastic leukemia. Hematol Oncol 2021; 39:364-379. [PMID: 33497493 PMCID: PMC8451758 DOI: 10.1002/hon.2840] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 01/07/2023]
Abstract
Wnt/Fzd signaling has been implicated in hematopoietic stem cell maintenance and in acute leukemia establishment. In our previous work, we described a recurrent rearrangement involving the WNT10B locus (WNT10BR), characterized by the expression of WNT10BIVS1 transcript variant, in acute myeloid leukemia. To determine the occurrence of WNT10BR in T‐cell acute lymphoblastic leukemia (T‐ALL), we retrospectively analyzed an Italian cohort of patients (n = 20) and detected a high incidence (13/20) of WNT10BIVS1 expression. To address genes involved in WNT10B molecular response, we have designed a Wnt‐targeted RNA sequencing panel. Identifying Wnt agonists and antagonists, it results that the expression of FZD6, LRP5, and PROM1 genes stands out in WNT10BIVS1 positive patients compared to negative ones. Using MOLT4 and MUTZ‐2 as leukemic cell models, which are characterized by the expression of WNT10BIVS1, we have observed that WNT10B drives major Wnt activation to the FZD6 receptor complex through receipt of ligand. Additionally, short hairpin RNAs (shRNAs)‐mediated gene silencing and small molecule‐mediated inhibition of WNTs secretion have been observed to interfere with the WNT10B/FZD6 interaction. We have therefore identified that WNT10BIVS1 knockdown, or pharmacological interference by the LGK974 porcupine (PORCN) inhibitor, reduces WNT10B/FZD6 protein complex formation and significantly impairs intracellular effectors and leukemic expansion. These results describe the molecular circuit induced by WNT10B and suggest WNT10B/FZD6 as a new target in the T‐ALL treatment strategy.
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Affiliation(s)
- Adriana Cassaro
- Department of Health Sciences, University of Milan, Milan, Italy.,Department of Oncology, Hematology Unit, Niguarda Hospital, Milan, Italy
| | - Giovanni Grillo
- Department of Oncology, Hematology Unit, Niguarda Hospital, Milan, Italy
| | - Marco Notaro
- Department of Computer Science "Giovanni degli Antoni", University of Milan, Milan, Italy
| | - Jessica Gliozzo
- Department of Computer Science "Giovanni degli Antoni", University of Milan, Milan, Italy
| | - Ilaria Esposito
- Department of Health Sciences, University of Milan, Milan, Italy
| | - Gianluigi Reda
- Department of Oncology, Hematology Unit, Ospedale Maggiore Policlinico, Milan, Italy
| | - Alessandra Trojani
- Department of Oncology, Hematology Unit, Niguarda Hospital, Milan, Italy
| | - Giorgio Valentini
- Department of Computer Science "Giovanni degli Antoni", University of Milan, Milan, Italy
| | | | - Roberto Cairoli
- Department of Oncology, Hematology Unit, Niguarda Hospital, Milan, Italy
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Caspi M, Wittenstein A, Kazelnik M, Shor-Nareznoy Y, Rosin-Arbesfeld R. Therapeutic targeting of the oncogenic Wnt signaling pathway for treating colorectal cancer and other colonic disorders. Adv Drug Deliv Rev 2021; 169:118-136. [PMID: 33346022 DOI: 10.1016/j.addr.2020.12.010] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 12/10/2020] [Accepted: 12/14/2020] [Indexed: 02/08/2023]
Abstract
The canonical Wnt pathway is one of the key cellular signaling cascades that regulates, via the transcriptional co-activator β-catenin, numerous embryogenic developmental processes, as well as tissue homeostasis. It is therefore not surprising that misregulation of the Wnt/β-catenin pathway has been implicated in carcinogenesis. Aberrant Wnt signaling has been reported in a variety of malignancies, and its role in both hereditary and sporadic colorectal cancer (CRC), has been the subject of intensive study. Interestingly, the vast majority of colorectal tumors harbor mutations in the tumor suppressor gene adenomatous polyposis coli (APC). The Wnt pathway is complex, and despite decades of research, the mechanisms that underlie its functions are not completely known. Thus, although the Wnt cascade is an attractive target for therapeutic intervention against CRC, one of the malignancies with the highest morbidity and mortality rates, achieving efficacy and safety is yet extremely challenging. Here, we review the current knowledge of the Wnt different epistatic signaling components and the mechanism/s by which the signal is transduced in both health and disease, focusing on CRC. We address some of the important questions in the field and describe various therapeutic strategies designed to combat unregulated Wnt signaling, the development of targeted therapy approaches and the emerging challenges that are associated with these advanced methods.
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Gautam DK, Chimata AV, Gutti RK, Paddibhatla I. Comparative hematopoiesis and signal transduction in model organisms. J Cell Physiol 2021; 236:5592-5619. [PMID: 33492678 DOI: 10.1002/jcp.30287] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 12/24/2020] [Accepted: 01/08/2021] [Indexed: 12/21/2022]
Abstract
Hematopoiesis is a continuous phenomenon involving the formation of hematopoietic stem cells (HSCs) giving rise to diverse functional blood cells. This developmental process of hematopoiesis is evolutionarily conserved, yet comparably different in various model organisms. Vertebrate HSCs give rise to all types of mature cells of both the myeloid and the lymphoid lineages sequentially colonizing in different anatomical tissues. Signal transduction in HSCs facilitates their potency and specifies branching of lineages. Understanding the hematopoietic signaling pathways is crucial to gain insights into their deregulation in several blood-related disorders. The focus of the review is on hematopoiesis corresponding to different model organisms and pivotal role of indispensable hematopoietic pathways. We summarize and discuss the fundamentals of blood formation in both invertebrate and vertebrates, examining the requirement of key signaling nexus in hematopoiesis. Knowledge obtained from such comparative studies associated with developmental dynamics of hematopoiesis is beneficial to explore the therapeutic options for hematopoietic diseases.
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Affiliation(s)
- Dushyant Kumar Gautam
- Department of Biochemistry, School of Life Sciences (SLS), University of Hyderabad, Hyderabad, Telangana, India
| | | | - Ravi Kumar Gutti
- Department of Biochemistry, School of Life Sciences (SLS), University of Hyderabad, Hyderabad, Telangana, India
| | - Indira Paddibhatla
- Department of Biochemistry, School of Life Sciences (SLS), University of Hyderabad, Hyderabad, Telangana, India
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Dai Y, Cheng Z, Fricke DR, Zhao H, Huang W, Zhong Q, Zhu P, Zhang W, Wu Z, Lin Q, Zhu H, Liu Y, Qian T, Fu L, Cui L, Zeng T. Prognostic role of Wnt and Fzd gene families in acute myeloid leukaemia. J Cell Mol Med 2021; 25:1456-1467. [PMID: 33417298 PMCID: PMC7875934 DOI: 10.1111/jcmm.16233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Revised: 12/09/2020] [Accepted: 12/11/2020] [Indexed: 01/18/2023] Open
Abstract
Wnt-Fzd signalling pathway plays a critical role in acute myeloid leukaemia (AML) progression and oncogenicity. There is no study to investigate the prognostic value of Wnt and Fzd gene families in AML. Our study screened 84 AML patients receiving chemotherapy only and 71 also undergoing allogeneic haematopoietic stem cell transplantation (allo-HSCT) from the Cancer Genome Atlas (TCGA) database. We found that some Wnt and Fzd genes had significant positive correlations. The expression levels of Fzd gene family were independent of survival in AML patients. In the chemotherapy group, AML patients with high Wnt2B or Wnt11 expression had significantly shorter event-free survival (EFS) and overall survival (OS); high Wnt10A expressers had significantly longer OS than the low expressers (all P < .05), whereas, in the allo-HSCT group, the expression levels of Wnt gene family were independent of survival. We further found that high expression of Wnt10A and Wnt11 had independent prognostic value, and the patients with high Wnt10A and low Wnt11 expression had the longest EFS and OS in the chemotherapy group. Pathway enrichment analysis showed that genes related to Wnt10A, Wnt11 and Wnt 2B were mainly enriched in 'cell morphogenesis involved in differentiation', 'haematopoietic cell lineage', 'platelet activation, signalling and aggregation' and 'mitochondrial RNA metabolic process' signalling pathways. Our results indicate that high Wnt2B and Wnt11 expression predict poor prognosis, and high Wnt10A expression predicts favourable prognosis in AML, but their prognostic effects could be neutralized by allo-HSCT. Combined Wnt10A and Wnt11 may be a novel prognostic marker in AML.
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Affiliation(s)
- Yifeng Dai
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhiheng Cheng
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Doerte R Fricke
- Department of Genetics, LSU Health Sciences Center, New Orleans, LA, USA
| | - Hongyou Zhao
- Institute of Engineering Medicine, Beijing Institute of Technology, Beijing, China
| | - Wenhui Huang
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qingfu Zhong
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Pei Zhu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Wenjuan Zhang
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Zhihua Wu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qing Lin
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Huoyan Zhu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yan Liu
- Translational Medicine Center, Huaihe Hospital of Henan University, Kaifeng, China
| | - Tingting Qian
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Lin Fu
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.,Department of Hematology, Huaihe Hospital of Henan University, Kaifeng, China.,Guangdong Provincial Education Department Key Laboratory of Nano-Immunoregulation Tumor Microenvironment, The Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, China
| | - Longzhen Cui
- Translational Medicine Center, Huaihe Hospital of Henan University, Kaifeng, China
| | - Tiansheng Zeng
- Department of Hematology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.,Translational Medicine Center, State Key Laboratory of Respiratory Disease, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Lin Z, Yang F, Lu D, Sun W, Zhu G, Lan B. Knockdown of NCOA2 Inhibits the Growth and Progression of Gastric Cancer by Affecting the Wnt Signaling Pathway-Related Protein Expression. Technol Cancer Res Treat 2021; 19:1533033820928072. [PMID: 32489143 PMCID: PMC7273340 DOI: 10.1177/1533033820928072] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Objective: The aim of the study is to determine the role of nuclear receptor coactivator
2 in cell proliferation and invasion ability of gastric cancer cells and to
explore its possible mechanisms. Methods: Immunohistochemical staining was used to determine NCOA2
gene expression in gastric cancer. Western blotting was used to detect Wnt
signal pathways–related protein expression. Colony formation assays, Cell
Counting Kit-8 assays, and transwell assays were used to determine cell
proliferation, metastasis, and invasion ability of gastric cancer cells. A
flow cytometric apoptosis tests determine gastric cancer cell apoptosis
ability after inhibition of the expression of nuclear receptor coactivator
2. Subcutaneous mouse models were used to determine the gastric cancer
growth and peritoneal metastasis differences after inhibition the expression
of nuclear receptor coactivator 2. Results: The expression of nuclear receptor coactivator 2 in gastric cancer cells is
high (P < .01), including lymph node metastasis, TNM
staging, and gender differences in nuclear receptor coactivator 2 expression
were statistically significant (P < .01). Short
interfering nuclear receptor coactivator 2 could inhibit the proliferation
and invasion ability of gastric cancer cells. Short interfering nuclear
receptor coactivator 2 promotes the apoptosis of gastric cancer cells.
Animal experiments showed that short interfering nuclear receptor
coactivator 2 could inhibit the growth and invasion of gastric
cancer-transplantable tumors. Knockdown of the expression of nuclear
receptor coactivator 2 inhibited the Wnt/β-catenin signaling pathway in the
gastric cancer cells. Conclusions: Knockdown of the expression of nuclear receptor coactivator 2 can inhibit the
proliferation and invasion of human gastric cancer in vitro
and in vivo. The underlying mechanism of NOCA2 affects the
Wnt signaling pathway.
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Affiliation(s)
- Zhenlv Lin
- Department of Emergency Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Fan Yang
- Department of Pediatric Surgery, First Hospital of Quanzhou, Fujian Medical University, Quanzhou, China
| | - Dong Lu
- Department of Gastrointestinal Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Wenjie Sun
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Guangwei Zhu
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | - Bin Lan
- Department of Gastroenterological Surgery, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China
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39
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So EY, Jeong EM, Wu KQ, Dubielecka PM, Reginato AM, Quesenberry PJ, Liang OD. Sexual dimorphism in aging hematopoiesis: an earlier decline of hematopoietic stem and progenitor cells in male than female mice. Aging (Albany NY) 2020; 12:25939-25955. [PMID: 33378745 PMCID: PMC7803521 DOI: 10.18632/aging.202167] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 10/20/2020] [Indexed: 12/27/2022]
Abstract
Adult hematopoietic stem and progenitor cells (HSPCs) reside in the bone marrow (BM) ensuring homeostasis of blood production and immune response throughout life. Sex differences in immunocompetence and mortality are well-documented in humans. However, whether HSPCs behave dimorphically between sexes during aging remains unknown. Here, we show that a significant expansion of BM-derived HSPCs occurs in the middle age of female but in the old age of male mice. We then show that a decline of HSPCs in male mice, as indicated by the expression levels of select hematopoietic genes, occurs much earlier in the aging process than that in female mice. Sex-mismatched heterochronic BM transplantations indicate that the middle-aged female BM microenvironment plays a pivotal role in sustaining hematopoietic gene expression during aging. Furthermore, a higher concentration of the pituitary sex hormone follicle-stimulating hormone (FSH) in the serum and a concomitant higher expression of its receptor on HSPCs in the middle-aged and old female mice than age-matched male mice, suggests that FSH may contribute to the sexual dimorphism in aging hematopoiesis. Our study reveals that HSPCs in the BM niches are possibly regulated in a sex-specific manner and influenced differently by sex hormones during aging hematopoiesis.
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Affiliation(s)
- Eui-Young So
- Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Euy-Myoung Jeong
- Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Keith Q Wu
- Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Patrycja M Dubielecka
- Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Anthony M Reginato
- Division of Rheumatology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Peter J Quesenberry
- Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
| | - Olin D Liang
- Division of Hematology/Oncology, Department of Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, Rhode Island 02903, USA
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Ratti S, Lonetti A, Follo MY, Paganelli F, Martelli AM, Chiarini F, Evangelisti C. B-ALL Complexity: Is Targeted Therapy Still A Valuable Approach for Pediatric Patients? Cancers (Basel) 2020; 12:cancers12123498. [PMID: 33255367 PMCID: PMC7760974 DOI: 10.3390/cancers12123498] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2020] [Revised: 11/17/2020] [Accepted: 11/20/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary B-ALL is the more frequent childhood malignancy. Even though significant improvements in patients’ survival, some pediatric B-ALL have still poor prognosis and novel strategies are needed. Recently, new genetic abnormalities and altered signaling pathways have been described, defining novel B-ALL subtypes.Innovative targeted therapeutic drugs may potentially show a great impact on the treatment of B-ALL subtypes, offering an important chance to block multiple signaling pathways and potentially improving the clinical management of B-ALL younger patients, especially for the new identified subtypes that lack efficient chemotherapeutic protocols. In this review, we shed light on the up-to-date knowledge of the novel childhood B-ALL subtypes and the altered signaling pathways that could become new druggable targets. Abstract B-cell acute lymphoblastic leukemia (B-ALL) is a hematologic malignancy that arises from the clonal expansion of transformed B-cell precursors and predominately affects childhood. Even though significant progresses have been made in the treatment of B-ALL, pediatric patients’ outcome has to be furtherly increased and alternative targeted treatment strategies are required for younger patients. Over the last decade, novel approaches have been used to understand the genomic landscape and the complexity of the molecular biology of pediatric B-ALL, mainly next generation sequencing, offering important insights into new B-ALL subtypes, altered pathways, and therapeutic targets that may lead to improved risk stratification and treatments. Here, we will highlight the up-to-date knowledge of the novel B-ALL subtypes in childhood, with particular emphasis on altered signaling pathways. In addition, we will discuss the targeted therapies that showed promising results for the treatment of the different B-ALL subtypes.
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Affiliation(s)
- Stefano Ratti
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (S.R.); (M.Y.F.); (F.P.); (A.M.M.)
| | - Annalisa Lonetti
- Giorgio Prodi Cancer Research Center, S. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti, 11, 40138 Bologna, Italy;
| | - Matilde Y. Follo
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (S.R.); (M.Y.F.); (F.P.); (A.M.M.)
| | - Francesca Paganelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (S.R.); (M.Y.F.); (F.P.); (A.M.M.)
| | - Alberto M. Martelli
- Department of Biomedical and Neuromotor Sciences, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy; (S.R.); (M.Y.F.); (F.P.); (A.M.M.)
| | - Francesca Chiarini
- CNR Institute of Molecular Genetics Luigi Luca Cavalli-Sforza, Via di Barbiano 1/10, 40136 Bologna, Italy
- IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136 Bologna, Italy
- Correspondence: (F.C.); (C.E.); Tel.: +39-051-209-1581 (F.C.); +39-051-209-1581 (C.E.)
| | - Camilla Evangelisti
- CNR Institute of Molecular Genetics Luigi Luca Cavalli-Sforza, Via di Barbiano 1/10, 40136 Bologna, Italy
- IRCCS Istituto Ortopedico Rizzoli, Via Di Barbiano 1/10, 40136 Bologna, Italy
- Correspondence: (F.C.); (C.E.); Tel.: +39-051-209-1581 (F.C.); +39-051-209-1581 (C.E.)
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Iron Overload Impairs Bone Marrow Mesenchymal Stromal Cells from Higher-Risk MDS Patients by Regulating the ROS-Related Wnt/ β-Catenin Pathway. Stem Cells Int 2020; 2020:8855038. [PMID: 33178287 PMCID: PMC7648692 DOI: 10.1155/2020/8855038] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 09/11/2020] [Accepted: 10/15/2020] [Indexed: 12/15/2022] Open
Abstract
The bone marrow microenvironment plays important roles in the progression of the myelodysplastic syndrome (MDS). The higher incidence of ASXL1 and TET2 gene mutations in our iron overload (IO) MDS patients suggests that IO may be involved in the pathogenesis of MDS. The effects of IO damaging bone marrow mesenchymal stromal cells (MSCs) from higher-risk MDS patients were investigated. In our study, IO decreased the quantity and weakened the abilities of proliferation and differentiation of MSCs, and it inhibited the gene expressions of VEGFA, CXCL12, and TGF-β1 in MSCs regulating hematopoiesis. The increased level of reactive oxygen species (ROS) in MSCs caused by IO might be inducing apoptosis by activating caspase3 signals and involving in MDS progression by activating β-catenin signals. The damages of MSCs caused by IO could be partially reversed by an antioxidant or an iron chelator. Furthermore, the MSCs in IO MDS/AML patients had increased levels of ROS and apoptosis, and the expressions of caspase3 and β-catenin were increased even further. In conclusion, IO affects gene stability in higher-risk MDS patients and impairs MSCs by inducing ROS-related apoptosis and activating the Wnt/β-catenin signaling pathway, which could be partially reversed by an antioxidant or an iron chelator.
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42
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Hu N, Yu T, Chen J, Zheng S, Yan H, Duan J. Oxycodone stimulates normal and malignant hematopoietic progenitors via opioid-receptor-independent-β-catenin activation. Biochem Biophys Res Commun 2020; 533:1457-1463. [PMID: 33268026 DOI: 10.1016/j.bbrc.2020.10.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 10/23/2022]
Abstract
Oxycodone is a common type of opioid used for the treatment of moderate to severe pain. Besides its analgesic effects on neuron cells, the effects of oxycodone on other cell types are yet to be elucidated. We previously demonstrated that oxycodone displayed both pro- and anti-cancer effects on bulk cancer cells. This work further investigated the effects of oxycodone on normal and malignant hematopoietic stem cells. Using hematopoietic CD34+ cells isolated from normal bone marrow (NBM) or patients with acute myeloid leukemia (AML), we showed that oxycodone activates hematopoietic cells regardless of cell development stage and malignant status. Oxycodone dose-dependently increases colony formation and self-renewal capacity of NBM and AML stem/progenitor cells, and promotes proliferation of AML bulk cells. NBM stem/progenitor cells are more sensitive to oxycodone than AML counterparts. In addition, oxycodone alleviates chemotherapy drug-induced toxicity in AML stem/progenitor cells. Mechanism studies demonstrate that oxycodone acts on hematopoietic cells in an opioid-receptor-independent manner. Oxycodone did not affect epithelial growth factor receptor (EGFR) signaling neither but stimulated Wnt/β-catenin signaling. Rescue studies via depleting β-catenin using genetic and pharmacological approaches confirmed that β-catenin was required for the activation of hematopoietic cells induced by oxycodone. Our work demonstrates 1) the protective role of oxycodone in malignant hematopoietic cells from chemotherapy; 2) stimulatory effects of oxycodone in normal hematopoietic stem cells; and 3) ability of oxycodone in Wnt signaling activation.
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Affiliation(s)
- Nianchun Hu
- Department of Anesthesiology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Ting Yu
- Department of Anesthesiology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Jingli Chen
- Department of Anesthesiology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shirong Zheng
- Department of Paediatrics, The Second Staff Hospital of Wuhan Iron and Steel Group Corporation, Wuhan, Hubei Province, China
| | - Hong Yan
- Department of Anesthesiology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Ji'an Duan
- Department of Anesthesiology, Wuhan Central Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China.
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Chattopadhyay S, Law S. Morphogen signaling by Wnt/β-catenin pathway and microenvironmental alteration in the bone marrow of agricultural pesticide exposure-induced experimental aplastic anemia. J Biochem Mol Toxicol 2020; 34:e22523. [PMID: 32410290 DOI: 10.1002/jbt.22523] [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: 10/12/2019] [Revised: 03/14/2020] [Accepted: 04/27/2020] [Indexed: 11/08/2022]
Abstract
The etiologic link between pesticide toxicity and aplastic anemia in agricultural and agro-industrial setting has been frequently reported in epidemiological studies conducted worldwide. Chronic pesticide toxicity causes long-term bone marrow injury and perturbs the normal hematopoietic physiology, including survival of hematopoietic progenitor cells and bone marrow's blood cell forming ability. The purpose of this study is to understand the mechanism of pesticide toxicity-mediated bone marrow aplasia by studying Wnt/β-catenin signaling pathway and microenvironmental stromal components. An agricultural pesticide formulation comprising of cypermethrin, chlorpyriphos, and hexaconazole was used to induce bone marrow aplasia in inbred Swiss albino mice. Marrow failure followed by the onset of aplastic condition was confirmed by pancytopenic peripheral blood and hypocellular bone marrow filled with adipocytes. Significant downregulation of canonical Wnt/β-catenin signaling was identified by expression analysis of Wnt3a, β-catenin, and telomerase reverse transcriptase in the aplastic bone marrow hematopoietic stem/progenitor compartment. Along with signaling deregulation, disruption in both the osteoblastic and vascular stromal components was observed in the pesticide-exposed bone marrow microenvironment when compared to control. In this study, we tried to establish the correlation among disease pathophysiology, signaling deregulation in the hematopoietic cells, and bone marrow microenvironmental alteration during environmental exposure-mediated aplastic hematopoietic catastrophe, which may shed light on the unexplored mechanistic perspective of this fatal blood disease.
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Affiliation(s)
- Sukalpa Chattopadhyay
- Stem Cell Research and Application Unit, Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India
| | - Sujata Law
- Stem Cell Research and Application Unit, Department of Biochemistry and Medical Biotechnology, Calcutta School of Tropical Medicine, Kolkata, West Bengal, India
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44
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Ruan Y, Kim HN, Ogana H, Kim YM. Wnt Signaling in Leukemia and Its Bone Marrow Microenvironment. Int J Mol Sci 2020; 21:ijms21176247. [PMID: 32872365 PMCID: PMC7503842 DOI: 10.3390/ijms21176247] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 08/16/2020] [Accepted: 08/24/2020] [Indexed: 12/19/2022] Open
Abstract
Leukemia is an aggressive hematologic neoplastic disease. Therapy-resistant leukemic stem cells (LSCs) may contribute to the relapse of the disease. LSCs are thought to be protected in the leukemia microenvironment, mainly consisting of mesenchymal stem/stromal cells (MSC), endothelial cells, and osteoblasts. Canonical and noncanonical Wnt pathways play a critical role in the maintenance of normal hematopoietic stem cells (HSC) and LSCs. In this review, we summarize recent findings on the role of Wnt signaling in leukemia and its microenvironment and provide information on the currently available strategies for targeting Wnt signaling.
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Affiliation(s)
- Yongsheng Ruan
- Department of Pediatrics, Division of Hematology, Oncology, Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027, USA; (Y.R.); (H.N.K.); (H.O.)
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Hye Na Kim
- Department of Pediatrics, Division of Hematology, Oncology, Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027, USA; (Y.R.); (H.N.K.); (H.O.)
| | - Heather Ogana
- Department of Pediatrics, Division of Hematology, Oncology, Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027, USA; (Y.R.); (H.N.K.); (H.O.)
| | - Yong-Mi Kim
- Department of Pediatrics, Division of Hematology, Oncology, Blood and Marrow Transplantation, Children’s Hospital Los Angeles, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA 90027, USA; (Y.R.); (H.N.K.); (H.O.)
- Correspondence:
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Taherkhani F, Hosseini KM, Zebardast S, Chegini KG, Gheibi N. Anti proliferative and apoptotic effects on pancreatic cancer cell lines indicate new roles for ANGPTL8 (Betatrophin). Genet Mol Biol 2020; 43:e20190196. [PMID: 32745158 PMCID: PMC7416753 DOI: 10.1590/1678-4685-gmb-2019-0196] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Accepted: 05/31/2020] [Indexed: 11/25/2022] Open
Abstract
Despite considerable advances, the treatment of pancreatic cancer (PC) still
requires much effort. Unusual regulation of the Wnt and apoptotic signaling
pathways is widespread in cancer incidence. For instance, the
WIF1 (Wnt inhibitory factor 1) gene is down-regulated in
many cancers. The purpose of this study was to determine the effects of
recombinant Betatrophin, a recently discovered hormone, on MiaPaca-II and
Panc-1 pancreatic cell lines. Various concentrations of
Betatrophin were added to MiaPaca-II and Panc-1 pancreatic cell
lines during periods of 24 , 48, and 72 h. The MTT assay was applied to
investigate cell proliferation after treatment. The rate of apoptotic cells was
assessed using double-staining flow cytometry, and the expression levels of the
WIF1 gene and Bcl2 protein was observed by real-time PCR
and western blotting, respectively. The findings of this study suggest that
Betatrophin has an anti-proliferative effect on both MiaPaca-II and Panc-1 cell
lines, in line with the up-regulation of WIF1 as a tumor
suppressor gene. Moreover, the induction of apoptosis by ANGPTL8 occurred by the
down-regulation of Bcl2. Thus, Betatrophin can be proposed as a potential
therapeutic drug for treating pancreatic cancer.
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Affiliation(s)
| | | | - Sanaz Zebardast
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Koorosh Goodarzvand Chegini
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Nematollah Gheibi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Diseases, Qazvin University of Medical Sciences, Qazvin, Iran
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Ryk modulates the niche activity of mesenchymal stromal cells by fine-tuning canonical Wnt signaling. Exp Mol Med 2020; 52:1140-1151. [PMID: 32724069 PMCID: PMC8080773 DOI: 10.1038/s12276-020-0477-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 04/02/2020] [Accepted: 04/02/2020] [Indexed: 12/12/2022] Open
Abstract
The importance of modulating the intensity of Wnt signaling has been highlighted in various biological models, but their mechanisms remain unclear. In this study, we found that Ryk—an atypical Wnt receptor with a pseudokinase domain—has a Wnt-modulating effect in bone marrow stromal cells to control hematopoiesis-supporting activities. We first found that Ryk is predominantly expressed in the mesenchymal stromal cells (MSCs) of the bone marrow (BM) compared with hematopoietic cells. Downregulation of Ryk in MSCs decreased their clonogenic activity and ability to support self-renewing expansion of primitive hematopoietic progenitors (HPCs) in response to canonical Wnt ligands. In contrast, under high concentrations of Wnt, Ryk exerted suppressive effects on the transactivation of target genes and HPC-supporting effects in MSCs, thus fine-tuning the signaling intensity of Wnt in BM stromal cells. This ability of Ryk to modulate the HPC-supporting niche activity of MSCs was abrogated by induction of deletion mutants of Ryk lacking the intracellular domain or extracellular domain, indicating that the pseudokinase-containing intracellular domain mediates the Wnt-modulating effects in response to extracellular Wnt ligands. These findings indicate that the ability of the BM microenvironment to respond to extracellular signals and support hematopoiesis may be fine-tuned by Ryk via modulation of Wnt signaling intensity to coordinate hematopoietic activity. Steady production of immune and blood cells depends on a signaling protein that helps maintain stable stem cell populations within the bone marrow. Hematopoietic stem cells (HSCs), which give rise to blood cells, reside within a supportive “niche” surrounded by mesenchymal stromal cells (MSCs), with extensive communication between the two populations. Researchers led by Il-Hoan Oh at The Catholic University of Korea, Seoul, have now identified a mechanism that MSCs employ to stabilize the niche environment through fine-tuning the signaling intensity of Wnt. Oh and colleagues focused on a signaling pathway that controls the undifferentiated state of HSCs, and showed that these signals are specifically modulated by an MSC protein known as Ryk. Without Ryk, MSCs can no longer promote HSC proliferation. However, when these signals are excessively strong, Ryk helps suppress proliferation to keep HSC numbers under control.
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Wang B, Wang M, Li X, Yang M, Liu L. Variations in the Wnt/β-Catenin Pathway Key Genes as Predictors of Cervical Cancer Susceptibility . Pharmgenomics Pers Med 2020; 13:157-165. [PMID: 32547159 PMCID: PMC7247596 DOI: 10.2147/pgpm.s248548] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 04/22/2020] [Indexed: 12/24/2022] Open
Abstract
Background Cervical cancer is the fourth most common and fatal tumor among women worldwide. The Wnt/β-catenin signaling pathway was etiologically involved in the cervical cancer model. Herein, we aimed to investigate whether germline genetic variations within the Wnt/β-catenin pathway can be genetic risk factors of cervical cancer. Patients and Methods A total of 305 samples (147 patients, 158 controls) were included. Eight genetic variations located in APC (rs454886), GSK3β (rs3755557), CTNNB1 (rs11564475, rs1798802, rs3864004, rs2293303, and rs4135385), and TCF7L2 (rs7903146) were genotyped via Sanger sequencing. The χ2 test and non-conditional logistic regression were used in the single-locus analysis. Gene–gene interactions and haplotype construction in case–control samples were performed by the GMDR method and Haploview software, respectively. Results The frequency of CTNNB1 rs1798802 GA+AA genotype was significantly lower in cervical cancer patients adjusted for age (OR=0.626, 95% CI=0.398–0.984). The mutant alleles of rs3864004 (A) and rs2293303 (T) located in CTNNB1 showed 1.513 (1.038–2.207), and 1.654 (1.020–2.683) fold increased risk of cervical cancer, respectively. Haplotype analysis showed no association between haplotypes of the CTNNB1 gene and cervical cancer risk. No significant contribution of interactions among genes in the Wnt pathway was identified. Conclusion We concluded that the genetic variants in the CTNNB1 gene might contribute to the development of cervical cancer.
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Affiliation(s)
- Bingqi Wang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People’s Republic of China
| | - Min Wang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People’s Republic of China
- Correspondence: Min Wang Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, 139 Middle Renmin Road, Changsha410011, Hunan, People’s Republic of China Tel/Fax +86 132 9869 7558 Email
| | - Xianping Li
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People’s Republic of China
| | - Min Yang
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People’s Republic of China
| | - Lei Liu
- Department of Laboratory Medicine, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, People’s Republic of China
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Demirci S, Gudmundsdottir B, Li Q, Haro-Mora JJ, Nassehi T, Drysdale C, Yapundich M, Gamer J, Seifuddin F, Tisdale JF, Uchida N. βT87Q-Globin Gene Therapy Reduces Sickle Hemoglobin Production, Allowing for Ex Vivo Anti-sickling Activity in Human Erythroid Cells. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 17:912-921. [PMID: 32405513 PMCID: PMC7210457 DOI: 10.1016/j.omtm.2020.04.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 04/13/2020] [Indexed: 12/31/2022]
Abstract
Lentiviral addition of βT87Q-globin, a modified β-globin with an anti-sickling mutation, is currently being used in gene therapy trials for sickle cell disease (SCD) and β-thalassemia patients. βT87Q-globin interferes with sickle hemoglobin (HbS) polymerization. Here, we generated the SCD mutation in an immortalized human erythroid cell line (HUDEP-2) to investigate the anti-sickling activity of βT87Q-globin. Sickle HUDEP-2 (sHUDEP-2) cells produced robust HbS after differentiation and sickled under deoxygenated conditions, comparable with SCD CD34+ progeny. Lentiviral transduction provided 9.5–26.8 pg/cell βT87Q-globin (R2 = 0.83) in a vector copy number (VCN)-dependent manner, resulting in a significant reduction of sickling ratios (R2 = 0.92). Interestingly, βT87Q-globin transduction markedly reduced endogenous βS-globin (R2 = 0.84) to an undetectable level (0.4–16.8 pg/cell) in sHUDEP-2 cells, as well as endogenous β-globin in human CD34+ cell-derived erythroid cells. RNA sequencing (RNA-seq) analysis with βT87Q-transduced sHUDEP-2 and human CD34+-derived cells revealed activation of inflammation- and proliferation-related programs, suggesting minimal changes in background gene expression except for βT87Q-globin expression and endogenous β/βS-globin suppression. In summary, using sHUDEP-2 and CD34+-derived cells, we demonstrated that lentiviral addition of βT87Q-globin strongly reduced endogenous β-/βS-globin expression, resulting in an anti-sickling effect. Our findings should be helpful to understand the anti-sickling effects of therapeutic genes in SCD gene therapy.
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Affiliation(s)
- Selami Demirci
- Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Bjorg Gudmundsdottir
- Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Quan Li
- Laboratory of Chemical Physics, NIDDK, NIH, Bethesda, MD, USA
| | - Juan J Haro-Mora
- Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Tina Nassehi
- Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Claire Drysdale
- Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Morgan Yapundich
- Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Jackson Gamer
- Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Fayaz Seifuddin
- Bioinformatics and Computational Biology Laboratory, NHLBI, NIH, Bethesda, MD, USA
| | - John F Tisdale
- Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
| | - Naoya Uchida
- Cellular and Molecular Therapeutics Branch, National Heart Lung and Blood Institutes (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD, USA
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Sweeney K, Cameron ER, Blyth K. Complex Interplay between the RUNX Transcription Factors and Wnt/β-Catenin Pathway in Cancer: A Tango in the Night. Mol Cells 2020; 43:188-197. [PMID: 32041394 PMCID: PMC7057843 DOI: 10.14348/molcells.2019.0310] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 12/19/2019] [Indexed: 12/15/2022] Open
Abstract
Cells are designed to be sensitive to a myriad of external cues so they can fulfil their individual destiny as part of the greater whole. A number of well-characterised signalling pathways dictate the cell's response to the external environment and incoming messages. In healthy, well-ordered homeostatic systems these signals are tightly controlled and kept in balance. However, given their powerful control over cell fate, these pathways, and the transcriptional machinery they orchestrate, are frequently hijacked during the development of neoplastic disease. A prime example is the Wnt signalling pathway that can be modulated by a variety of ligands and inhibitors, ultimately exerting its effects through the β-catenin transcription factor and its downstream target genes. Here we focus on the interplay between the three-member family of RUNX transcription factors with the Wnt pathway and how together they can influence cell behaviour and contribute to cancer development. In a recurring theme with other signalling systems, the RUNX genes and the Wnt pathway appear to operate within a series of feedback loops. RUNX genes are capable of directly and indirectly regulating different elements of the Wnt pathway to either strengthen or inhibit the signal. Equally, β-catenin and its transcriptional co-factors can control RUNX gene expression and together they can collaborate to regulate a large number of third party co-target genes.
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Affiliation(s)
- Kerri Sweeney
- CRUK Beatson Institute, Garscube Estate, Glasgow G6 BD, UK
| | - Ewan R. Cameron
- Glasgow Veterinary School, University of Glasgow, Glasgow G61 1QH, UK
| | - Karen Blyth
- CRUK Beatson Institute, Garscube Estate, Glasgow G6 BD, UK
- Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
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The Role Played by Wnt/β-Catenin Signaling Pathway in Acute Lymphoblastic Leukemia. Int J Mol Sci 2020; 21:ijms21031098. [PMID: 32046053 PMCID: PMC7037748 DOI: 10.3390/ijms21031098] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 01/28/2020] [Accepted: 02/05/2020] [Indexed: 12/15/2022] Open
Abstract
Acute lymphoblastic leukemia (ALL) is an aggressive hematologic neoplastic disorder that arises from the clonal expansion of transformed T-cell or B-cell precursors. Thanks to progress in chemotherapy protocols, ALL outcome has significantly improved. However, drug-resistance remains an unresolved issue in the treatment of ALL and toxic effects limit dose escalation of current chemotherapeutics. Therefore, the identification of novel targeted therapies to support conventional chemotherapy is required. The Wnt/β-catenin pathway is a conserved signaling axis involved in several physiological processes such as development, differentiation, and adult tissue homeostasis. As a result, deregulation of this cascade is closely related to initiation and progression of various types of cancers, including hematological malignancies. In particular, deregulation of this signaling network is involved in the transformation of healthy HSCs in leukemic stem cells (LSCs), as well as cancer cell multi-drug-resistance. This review highlights the recent findings on the role of Wnt/β-catenin in hematopoietic malignancies and provides information on the current status of Wnt/β-catenin inhibitors with respect to their therapeutic potential in the treatment of ALL.
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