|
1
|
Wu T, Sun Y, Wang D, Isaji T, Fukuda T, Suzuki C, Hanamatsu H, Nishikaze T, Tsumoto H, Miura Y, Furukawa JI, Gu J. The acetylglucosaminyltransferase GnT-Ⅲ regulates erythroid differentiation through ERK/MAPK signaling. J Biol Chem 2024; 300:108010. [PMID: 39571652 PMCID: PMC11699732 DOI: 10.1016/j.jbc.2024.108010] [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: 07/17/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 12/15/2024] Open
Abstract
Differentiation therapy is an alternative strategy used in treating chronic myelogenous leukemia to induce the differentiation of immature or cancerous cells toward mature cells and inhibit tumor cell proliferation. We aimed to explore N-glycans' roles in erythroid differentiation using the sodium butyrate (NaBu)-induced model of K562 cells (WT/NaBu cells). Here, using lectin blot, flow cytometry, real-time PCR, and mass spectrometry analyses, we demonstrated that the mRNA levels of N-acetylglucosaminyltransferase Ⅲ ((encoded by the MGAT3 gene) and its product (bisected N-glycans) were significantly increased during erythroid differentiation. To address the importance of GnTN-acetylglucosaminyltransferase-Ⅲ in this progress, we established a stable MGAT3 KO K562 cell line using the CRISPR/Cas9 technology. Compared to WT/NaBu cells, MGAT3 KO significantly impeded the progression of erythroid differentiation, as shown in decreased cell color and levels of erythroid markers, glycophorin A (CD235a), and β-globin. Consistently, MGAT3 KO mitigated the inhibitory impact of NaBu on cell proliferation. During induction, MGAT3 KO suppressed the cellular phosphorylated tyrosine and phospho-extracellular signal-regulated kinase (ERK)1/2 levels. Inhibition of the ERK/mitogen-activated protein kinase signaling pathway using U0126 blocked erythroid differentiation while concurrently suppressing the expression levels of MGAT3 and bisected N-glycans. Furthermore, the lack of bisecting GlcNAc modification on c-Kit and transferrin receptor 1 (CD71) suppressed cellular signaling and accelerated the degradation of the CD71 protein, respectively. Our study highlights the critical role of MGAT3 in regulating erythroid differentiation associated with the ERK/mitogen-activated protein kinase signaling pathway, which may shed light on identifying new differentiation therapy in chronic myelogenous leukemia.
Collapse
Affiliation(s)
- Tiangui Wu
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
| | - Yuhan Sun
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
| | - Dan Wang
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
| | - Tomoya Isaji
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
| | - Tomohiko Fukuda
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
| | - Chiharu Suzuki
- Division of Glyco-Systems Biology, Institute for Glyco-Core Research, Tokai National Higher Education and Research System, Nagoya, Japan
| | - Hisatoshi Hanamatsu
- Division of Glyco-Systems Biology, Institute for Glyco-Core Research, Tokai National Higher Education and Research System, Nagoya, Japan
| | - Takashi Nishikaze
- Solutions COE, Analytical & Measuring Instruments Division, Shimadzu Corporation, Kyoto, Japan
| | - Hiroki Tsumoto
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan
| | - Yuri Miura
- Research Team for Mechanism of Aging, Tokyo Metropolitan Institute for Geriatrics and Gerontology, Tokyo, Japan
| | - Jun-Ichi Furukawa
- Division of Glyco-Systems Biology, Institute for Glyco-Core Research, Tokai National Higher Education and Research System, Nagoya, Japan; Department of Orthopedic Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Jianguo Gu
- Division of Regulatory Glycobiology, Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan.
| |
Collapse
|
|
2
|
Lima MP, Hornsby BD, Lim CS, Cheatham TE. Molecular Modeling of Single- and Double-Hydrocarbon-Stapled Coiled-Coil Inhibitors against Bcr-Abl: Toward a Treatment Strategy for CML. J Phys Chem B 2024; 128:6476-6491. [PMID: 38951498 PMCID: PMC11247501 DOI: 10.1021/acs.jpcb.4c02699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/10/2024] [Accepted: 06/11/2024] [Indexed: 07/03/2024]
Abstract
The chimeric oncoprotein Bcr-Abl is the causative agent of virtually all chronic myeloid leukemias and a subset of acute lymphoblastic leukemias. As a result of the so-called Philadelphia chromosome translocation t(9;22), Bcr-Abl manifests as a constitutively active tyrosine kinase, which promotes leukemogenesis by activation of cell cycle signaling pathways. Constitutive and oncogenic activation is mediated by an N-terminal coiled-coil oligomerization domain in Bcr (Bcr-CC), presenting a therapeutic target for inhibition of Bcr-Abl activity toward the treatment of Bcr-Abl+ leukemias. Previously, we demonstrated that a rationally designed Bcr-CC mutant, CCmut3, exerts a dominant negative effect upon Bcr-Abl activity by preferential oligomerization with Bcr-CC. Moreover, we have shown that conjugation to a leukemia-specific cell-penetrating peptide (CPP-CCmut3) improves intracellular delivery and activity. However, our full-length CPP-CCmut3 construct (81 aa) is encumbered by an intrinsically high degree of conformational variability and susceptibility to proteolytic degradation relative to traditional small-molecule therapeutics. Here, we iterate a new generation of CCmut3 inhibitors against Bcr-CC-mediated Bcr-Abl assembly designed to address these constraints through incorporation of all-hydrocarbon staples spanning i and i + 7 positions in α-helix 2 (CPP-CCmut3-st). We utilize computational modeling and biomolecular simulation to evaluate single- and double-stapled CCmut3 candidates in silico for dynamics and binding energetics. We further model a truncated system characterized by the deletion of α-helix 1 and the flexible loop linker, which are known to impart high conformational variability. To study the impact of the N-terminal cyclic CPP toward model stability and inhibitor activity, we also model the full-length and truncated systems devoid of the CPP, with a cyclized CPP, and with an open-configuration CPP, for a total of six systems that comprise our library. From this library, we present lead-stapled peptide candidates to be synthesized and evaluated experimentally as our next iteration of inhibitors against Bcr-Abl.
Collapse
MESH Headings
- Fusion Proteins, bcr-abl/antagonists & inhibitors
- Fusion Proteins, bcr-abl/metabolism
- Fusion Proteins, bcr-abl/chemistry
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism
- Humans
- Protein Kinase Inhibitors/chemistry
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/metabolism
- Models, Molecular
- Molecular Dynamics Simulation
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/pharmacology
- Cell-Penetrating Peptides/chemistry
- Cell-Penetrating Peptides/pharmacology
- Cell-Penetrating Peptides/metabolism
Collapse
Affiliation(s)
- Maria
Carolina P. Lima
- Department
of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, United States
| | - Braxten D. Hornsby
- Department
of Molecular Pharmaceutics, University of
Utah, Salt Lake City, Utah 84112, United States
| | - Carol S. Lim
- Department
of Molecular Pharmaceutics, University of
Utah, Salt Lake City, Utah 84112, United States
| | - Thomas E. Cheatham
- Department
of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, United States
| |
Collapse
|
|
3
|
Vysochinskaya V, Dovbysh O, Gorshkov A, Brodskaia A, Dubina M, Vasin A, Zabrodskaya Y. Advancements and Future Prospects in Molecular Targeted and siRNA Therapies for Chronic Myeloid Leukemia. Biomolecules 2024; 14:644. [PMID: 38927048 PMCID: PMC11201692 DOI: 10.3390/biom14060644] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/24/2024] [Accepted: 05/27/2024] [Indexed: 06/28/2024] Open
Abstract
Chronic myeloid leukemia (CML) is an oncological myeloproliferative disorder that accounts for 15 to 20% of all adult leukemia cases. The molecular basis of this disease lies in the formation of a chimeric oncogene BCR-ABL1. The protein product of this gene, p210 BCR-ABL1, exhibits abnormally high constitutive tyrosine kinase activity. Over recent decades, several targeted tyrosine kinase inhibitors (TKIs) directed against BCR-ABL1 have been developed and introduced into clinical practice. These inhibitors suppress BCR-ABL1 activity through various mechanisms. Furthermore, the advent of RNA interference technology has enabled the highly specific inhibition of BCR-ABL1 transcript expression using small interfering RNA (siRNA). This experimental evidence opens avenues for the development of a novel therapeutic strategy for CML, termed siRNA therapy. The review delves into molecular genetic mechanisms underlying the pathogenesis of CML, challenges in CML therapy, potential molecular targets for drug development, and the latest results from the application of siRNAs in in vitro and in vivo CML models.
Collapse
MESH Headings
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/therapy
- Humans
- RNA, Small Interfering/genetics
- RNA, Small Interfering/therapeutic use
- Fusion Proteins, bcr-abl/genetics
- Fusion Proteins, bcr-abl/antagonists & inhibitors
- Fusion Proteins, bcr-abl/metabolism
- Molecular Targeted Therapy
- Animals
- Protein Kinase Inhibitors/therapeutic use
- Protein Kinase Inhibitors/pharmacology
- RNA Interference
Collapse
Affiliation(s)
- Vera Vysochinskaya
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia (Y.Z.)
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Ulitsa Prof. Popova, 197376 St. Petersburg, Russia
| | - Olesya Dovbysh
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia (Y.Z.)
| | - Andrey Gorshkov
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Ulitsa Prof. Popova, 197376 St. Petersburg, Russia
- Almazov National Research Centre, Akkuratova str. 2, 197341 St. Petersburg, Russia
| | - Alexandra Brodskaia
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia (Y.Z.)
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Ulitsa Prof. Popova, 197376 St. Petersburg, Russia
| | - Michael Dubina
- Russian Academy of Sciences, 14 Leninskiy pr., 119991 Moscow, Russia
| | - Andrey Vasin
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia (Y.Z.)
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Ulitsa Prof. Popova, 197376 St. Petersburg, Russia
| | - Yana Zabrodskaya
- Institute of Biomedical Systems and Biotechnology, Peter the Great Saint Petersburg Polytechnic University, 29 Ulitsa Polytechnicheskaya, 194064 St. Petersburg, Russia (Y.Z.)
- Smorodintsev Research Institute of Influenza, Russian Ministry of Health, 15/17 Ulitsa Prof. Popova, 197376 St. Petersburg, Russia
| |
Collapse
|
|
4
|
Dai C, Cui X, Wang J, Dong B, Gao H, Cheng M, Jiang F. CX‑5461 potentiates imatinib‑induced apoptosis in K562 cells by stimulating KIF1B expression. Exp Ther Med 2024; 27:107. [PMID: 38356673 PMCID: PMC10865453 DOI: 10.3892/etm.2024.12395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 11/29/2023] [Indexed: 02/16/2024] Open
Abstract
The selective RNA polymerase I inhibitor CX-5461 has been shown to be effective in treating some types of leukemic disorders. Emerging evidence suggests that combined treatments with CX-5461 and other chemotherapeutic agents may achieve enhanced effectiveness as compared with monotherapies. Currently, pharmacodynamic properties of the combination of CX-5461 with tyrosine kinase inhibitors remain to be explored. The present study tested whether CX-5461 could potentiate the effect of imatinib in the human chronic myeloid leukemia cell line K562, which is p53-deficient. It was demonstrated that CX-5461 at 100 nM, which was non-cytotoxic in K562 cells, potentiated the pro-apoptotic effect of imatinib. Mechanistically, the present study identified that the upregulated expression of kinesin family member 1B (KIF1B) gene might be involved in mediating the pro-apoptotic effect of imatinib/CX-5461 combination. Under the present experimental settings, however, neither CX-5461 nor imatinib alone exhibited a significant effect on KIF1B expression. Moreover, using other leukemic cell lines, it was demonstrated that regulation of KIF1B expression by imatinib/CX-5461 was not a ubiquitous phenomenon in leukemic cells and should be studied in a cell type-specific manner. In conclusion, the results suggested that the synergistic interaction between CX-5461 and imatinib may be of potential clinical value for the treatment of tyrosine kinase inhibitor-resistant chronic myeloid leukemia.
Collapse
Affiliation(s)
- Chaochao Dai
- Shandong Key Laboratory of Cardiovascular Proteomics and Department of Geriatric Medicine, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xiaopei Cui
- Shandong Key Laboratory of Cardiovascular Proteomics and Department of Geriatric Medicine, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Jie Wang
- Shandong Key Laboratory of Cardiovascular Proteomics and Department of Geriatric Medicine, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Bo Dong
- Department of Cardiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, P.R. China
| | - Haiqing Gao
- Shandong Key Laboratory of Cardiovascular Proteomics and Department of Geriatric Medicine, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Mei Cheng
- Shandong Key Laboratory of Cardiovascular Proteomics and Department of Geriatric Medicine, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Fan Jiang
- Shandong Key Laboratory of Cardiovascular Proteomics and Department of Geriatric Medicine, Qilu Hospital, Shandong University, Jinan, Shandong 250012, P.R. China
| |
Collapse
|
|
5
|
Lima MCP, Hornsby BD, Lim CS, Cheatham TE. Computational Modeling of Stapled Coiled-Coil Inhibitors Against Bcr-Abl: Toward a Treatment Strategy for CML. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.11.15.566894. [PMID: 38014060 PMCID: PMC10680756 DOI: 10.1101/2023.11.15.566894] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
The chimeric oncoprotein Bcr-Abl is the causative agent of virtually all chronic myeloid leukemias (CML) and a subset of acute lymphoblastic leukemias (ALL). As a result of the so-called Philadelphia Chromosome translocation t(9;22), Bcr-Abl manifests as a constitutively active tyrosine kinase which promotes leukemogenesis by activation of cell cycle signaling pathways. Constitutive and oncogenic activation is mediated by an N-terminal coiled-coil oligomerization domain in Bcr (Bcr-CC), presenting a therapeutic target for inhibition of Bcr-Abl activity toward the treatment of Bcr-Abl+ leukemias. Previously, we demonstrated that a rationally designed Bcr-CC mutant, CCmut3, exerts a dominant negative effect upon Bcr-Abl activity by preferential oligomerization with Bcr-CC. Moreover, we have shown conjugation to a leukemia-specific cell-penetrating peptide (CPP-CCmut3) improves intracellular delivery and activity. However, our full-length CPP-CCmut3 construct (81 aa) is encumbered by an intrinsically high degree of conformational variability and susceptibility to proteolytic degradation, relative to traditional small molecule therapeutics. Here, we iterate a new generation of our inhibitor against Bcr-CC mediated Bcr-Abl assembly that is designed to address these constraints through incorporation of all-hydrocarbon staples spanning i, i + 7 positions in helix α2 (CPP-CCmut3-st). We utilize computational modeling and biomolecular simulation to design and characterize single and double staple candidates in silico, evaluating binding energetics and building upon our seminal work modeling single hydrocarbon staples when applied to a truncated Bcr-CC sequence. This strategy enables us to efficiently build, characterize, and screen lead single/double stapled CPP-CCmut3-st candidates for experimental studies and validation in vitro and in vivo. In addition to full-length CPP-CCmut, we model a truncated system characterized by deletion of helix α1 and the flexible-loop linker, which are known to impart high conformational variability. To study the impact of the N-terminal cyclic CPP toward model stability and inhibitor activity, we also model the full-length and truncated systems without CPP, with cyclized CPP, and with linear CPP, for a total of six systems which comprise our library. From this library, we present lead stapled peptide candidates to be synthesized and evaluated experimentally as our next-generation inhibitors against Bcr-Abl.
Collapse
Affiliation(s)
- Maria Carolina P. Lima
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, United States
| | - Braxten D. Hornsby
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah 84112, United States
| | - Carol S. Lim
- Department of Molecular Pharmaceutics, University of Utah, Salt Lake City, Utah 84112, United States
| | - Thomas E. Cheatham
- Department of Medicinal Chemistry, University of Utah, Salt Lake City, Utah 84112, United States
| |
Collapse
|
|
6
|
Chronic Eosinophilic Leukemia Presenting as Cardiac Failure. Case Rep Hematol 2022; 2022:7841310. [PMID: 36568337 PMCID: PMC9788895 DOI: 10.1155/2022/7841310] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 11/13/2022] [Accepted: 12/02/2022] [Indexed: 12/23/2022] Open
Abstract
Chronic eosinophilic leukemia (CEL) is a rare chronic myeloproliferative disorder characterized by sustained eosinophilia. Although the incidence of CEL is uncertain, it can be clinically devastating as it has a propensity to affect several important organ systems. This is of particular significance in Sub-Saharan Africa where helminthic infections are a more prevalent cause of eosinophilia. To the best of our knowledge, we present the first reported case of CEL complicated by cardiac disease in a Ghanaian. He presented with a history of orthopnoea and dyspnoea on exertion, and examination revealed a pansystolic murmur over the mitral region and moderate splenomegaly. Good symptomatic control was achieved using hydroxyurea after which haematologic and cytogenetic remission was achieved after 12 weeks on a tyrosine kinase inhibitor. Physicians working in low resource environments should exclude clonality in patients presenting with eosinophilia and end-organ damage.
Collapse
|
|
7
|
Zhang L, Habeebu SSM, Li W. Prognostic and Predictive Biomarkers in Precursor B-cell Acute Lymphoblastic Leukemia. Leukemia 2022. [DOI: 10.36255/exon-publications-leukemia-biomarkers-lymphoblastic-leukemia] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
|
|
8
|
Wang X, Bajpai AK, Gu Q, Centeno A, Starlard-Davenport A, Prins P, Xu F, Lu L. A systems genetics approach delineates the role of Bcl2 in leukemia pathogenesis. Leuk Res 2022; 114:106804. [PMID: 35182904 PMCID: PMC9272521 DOI: 10.1016/j.leukres.2022.106804] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 01/11/2022] [Accepted: 02/06/2022] [Indexed: 01/11/2023]
Abstract
Leukemia is a group of malignancies of the blood forming tissues, and is characterized by the uncontrolled proliferation of blood cells. In the United States, it accounts for approximately 3.5% and 4% of all cancer-related incidences and mortalities, respectively. The current study aimed to explore the role of Bcl2 and associated genes in leukemia pathogenesis using a systems genetics approach. The transcriptome data from BXD Recombinant Inbred (RI) mice was analyzed to identify the expression of Bcl2 in myeloid cells. eQTL mapping was performed to select the potential chromosomal region and subsequently identify the candidate gene modulating the expression of Bcl2. Furthermore, gene enrichment and protein-protein interaction (PPI) analyses of the Bcl2-coexpressed genes were performed to demonstrate the role of Bcl2 in leukemia pathogenesis. The Bcl2-coexpressed genes were found to be enriched in various hematopoietic system related functions, and multiple pathways related to signaling, immune response, and cancer. The PPI network analysis demonstrated direct interaction of hematopoietic function related genes, such as Bag3, Bak1, Bcl2l11, Bmf, Mapk9, Myc, Ppp2r5c, and Ppp3ca with Bcl2. The eQTL mapping identified a 4.5 Mb genomic region on chromosome 11, potentially regulating the expression of Bcl2. A multi-criteria filtering process identified Top2a, among the genes located in the mapped locus, as the best candidate upstream regulator for Bcl2 expression variation. Hence, the current study provides better insights into the role of Bcl2 in leukemia pathogenesis and demonstrates the significance of our approach in gaining new knowledge on leukemia. Furthermore, our findings from the PPI network analysis and eQTL mapping provide supporting evidence of leukemia-associated genes, which can be further explored for their functional importance in leukemia. DATA AVAILABILITY: The myeloid cell transcriptomic data of the BXD mice used in this study can be accessed through our GeneNetwork (http://www.genenetwork.org) with the accession number of GN144.
Collapse
Affiliation(s)
- Xinfeng Wang
- Department of Hematology, Affiliated Hospital of Nantong University, Jiangsu, China
| | - Akhilesh Kumar Bajpai
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Qingqing Gu
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA,Department of Cardiology, Affiliated Hospital of Nantong University, Jiangsu 226001, China
| | - Arthur Centeno
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Athena Starlard-Davenport
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Pjotr Prins
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Fuyi Xu
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA; School of Pharmacy, Binzhou Medical University, Yantai, Shandong 264003, China.
| | - Lu Lu
- Department of Genetics, Genomics, and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
| |
Collapse
|
|
9
|
Targeting BCR-Abl in the treatment of Philadelphia-chromosome positive chronic myelogenous leukemia. Pharmacol Res 2022; 178:106156. [DOI: 10.1016/j.phrs.2022.106156] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 03/02/2022] [Indexed: 02/07/2023]
|
|
10
|
Sato-Otsubo A, Osumi T, Yoshida M, Iguchi A, Fukushima T, Nakabayashi K, Ogawa S, Hata K, Kato M. Genomic analysis of two rare cases of pediatric Ph-positive T-ALL. Pediatr Blood Cancer 2022; 69:e29427. [PMID: 34719840 DOI: 10.1002/pbc.29427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Accepted: 10/07/2021] [Indexed: 11/08/2022]
Affiliation(s)
- Aiko Sato-Otsubo
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.,Department of Pediatrics, The University of Tokyo, Tokyo, Japan
| | - Tomoo Osumi
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.,Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Masanori Yoshida
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Akihiro Iguchi
- Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.,Department of Pediatrics, Hokkaido University, Sapporo, Japan
| | - Takashi Fukushima
- Department of Pediatric Hematology and Oncology, Saitama Medical University International Medical Center, Saitama, Japan.,Department of Pediatrics, University of Tsukuba Hospital, Tsukuba, Japan
| | - Kazuhiko Nakabayashi
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Kyoto University, Kyoto, Japan.,Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto, Japan.,Department of Molecular Hematology, Karolinska Institute, Stockholm, Sweden
| | - Kenichiro Hata
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Motohiro Kato
- Department of Pediatric Hematology and Oncology Research, National Research Institute for Child Health and Development, Tokyo, Japan.,Department of Pediatrics, The University of Tokyo, Tokyo, Japan.,Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| |
Collapse
|
|
11
|
Mirzaei G, Petreaca RC. Distribution of copy number variations and rearrangement endpoints in human cancers with a review of literature. Mutat Res 2022; 824:111773. [PMID: 35091282 PMCID: PMC11301607 DOI: 10.1016/j.mrfmmm.2021.111773] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Revised: 12/08/2021] [Accepted: 12/10/2021] [Indexed: 12/13/2022]
Abstract
Copy number variations (CNVs) which include deletions, duplications, inversions, translocations, and other forms of chromosomal re-arrangements are common to human cancers. In this report we investigated the pattern of these variations with the goal of understanding whether there exist specific cancer signatures. We used re-arrangement endpoint data deposited on the Catalogue of Somatic Mutations in Cancers (COSMIC) for our analysis. Indeed, we find that human cancers are characterized by specific patterns of chromosome rearrangements endpoints which in turn result in cancer specific CNVs. A review of the literature reveals tissue specific mutations which either drive these CNVs or appear as a consequence of CNVs because they confer an advantage to the cancer cell. We also identify several rearrangement endpoints hotspots that were not previously reported. Our analysis suggests that in addition to local chromosomal architecture, CNVs are driven by the internal cellular or nuclear physiology of each cancer tissue.
Collapse
Affiliation(s)
- Golrokh Mirzaei
- Department of Computer Science and Engineering, The Ohio State University at Marion, Marion, OH, 43302, USA
| | - Ruben C Petreaca
- Department of Molecular Genetics, The Ohio State University at Marion, Marion, OH, 43302, USA; Cancer Biology Program, The Ohio State University James Comprehensive Cancer Center, Columbus, OH, 43210, USA.
| |
Collapse
|
|
12
|
Foo BJA, Eu JQ, Hirpara JL, Pervaiz S. Interplay between Mitochondrial Metabolism and Cellular Redox State Dictates Cancer Cell Survival. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:1341604. [PMID: 34777681 PMCID: PMC8580634 DOI: 10.1155/2021/1341604] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Revised: 09/30/2021] [Accepted: 10/04/2021] [Indexed: 02/06/2023]
Abstract
Mitochondria are the main powerhouse of the cell, generating ATP through the tricarboxylic acid cycle (TCA) and oxidative phosphorylation (OXPHOS), which drives myriad cellular processes. In addition to their role in maintaining bioenergetic homeostasis, changes in mitochondrial metabolism, permeability, and morphology are critical in cell fate decisions and determination. Notably, mitochondrial respiration coupled with the passage of electrons through the electron transport chain (ETC) set up a potential source of reactive oxygen species (ROS). While low to moderate increase in intracellular ROS serves as secondary messenger, an overwhelming increase as a result of either increased production and/or deficient antioxidant defenses is detrimental to biomolecules, cells, and tissues. Since ROS and mitochondria both regulate cell fate, attention has been drawn to their involvement in the various processes of carcinogenesis. To that end, the link between a prooxidant milieu and cell survival and proliferation as well as a switch to mitochondrial OXPHOS associated with recalcitrant cancers provide testimony for the remarkable metabolic plasticity as an important hallmark of cancers. In this review, the regulation of cell redox status by mitochondrial metabolism and its implications for cancer cell fate will be discussed followed by the significance of mitochondria-targeted therapies for cancer.
Collapse
Affiliation(s)
- Brittney Joy-Anne Foo
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
| | - Jie Qing Eu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
- Cancer Science Institute, NUS, Singapore, Singapore
| | | | - Shazib Pervaiz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, Singapore
- NUS Center for Cancer Research (N2CR), Yong Loo Lin School of Medicine, NUS, Singapore, Singapore
- NUS Medicine Healthy Longevity Program, Yong Loo Lin School of Medicine, NUS, Singapore, Singapore
- Integrative Sciences and Engineering Program, NUS Graduate School, NUS, Singapore, Singapore
- National University Cancer Institute, National University Health System, Singapore, Singapore
- Faculté de Médicine, Université de Paris, Paris, France
| |
Collapse
|
|
13
|
Zehnder M, Belibasakis GN. A critical analysis of research methods to study clinical molecular biomarkers in Endodontic research. Int Endod J 2021; 55 Suppl 1:37-45. [PMID: 34655496 PMCID: PMC9298367 DOI: 10.1111/iej.13647] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2021] [Accepted: 10/14/2021] [Indexed: 12/22/2022]
Abstract
The authors of this narrative review aimed to address various experimental methods and make recommendations for how research should move forward in the context of studying biomarkers in clinical Endodontic research. The approach adopted is exemplified using two prominent clinical problems, namely (a) the ‘reversible’ versus ‘irreversible’ pulpitis conundrum and (b) persistent idiopathic dentoalveolar pain (PIDAP). Pulpitis under deep caries or dentinal cracks is understood from a histological perspective, but clinical assessment tools to indicate irreversibly inflamed aspects of the dental pulp are elusive. PIDAP, on the other hand, is a diagnosis of exclusion; its pathophysiology is complex and not understood sufficiently to avoid unnecessary dental treatments. This review addresses how diagnostic biomarkers could further our understanding of those and other clinical problems, and how issues can be tackled from a methodological point of view. Hence, different methodological approaches to identify suitable diagnostic biomarker(s) or use known biomarkers are presented. The importance of asking a relevant research question, collecting the most suitable fluid and using the ideal collection vehicle for the research question under investigation is discussed based on the defined clinical problems.
Collapse
Affiliation(s)
- Matthias Zehnder
- Clinic of Conservative and Preventive Dentistry, University of Zürich Center of Dental Medicine, Zürich, Switzerland
| | - Georgios N Belibasakis
- Division of Oral Diseases, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden
| |
Collapse
|
|
14
|
Balzerano A, Paccosi E, Proietti-De-Santis L. Evolutionary Mechanisms of Cancer Suggest Rational Therapeutic Approaches. Cytogenet Genome Res 2021; 161:362-371. [PMID: 34461614 DOI: 10.1159/000516530] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Accepted: 03/25/2021] [Indexed: 11/19/2022] Open
Abstract
The goal in personalized therapeutic approaches for cancer medicine is to identify specific mutations with prognostic and therapeutic value in order to tailor the therapy for the single patient. The most powerful obstacle for personalized medicine arises from intratumor heterogeneity and clonal evolution, which can promote drug resistance. In this scenario, new technologies, such as next-generation sequencing, have emerged as a central diagnostic tool to profile cancer (epi)genomic landscapes. Therefore, a better understanding of the biological mechanisms underlying cancer evolution is mandatory and represents the current challenge to accurately predict whether cancer will recur after chemotherapy with the aim to tailor rational therapeutic approaches.
Collapse
Affiliation(s)
- Alessio Balzerano
- Unit of Molecular Genetics of Aging, Department of Ecology and Biology, University of Tuscia, Viterbo, Italy
| | - Elena Paccosi
- Unit of Molecular Genetics of Aging, Department of Ecology and Biology, University of Tuscia, Viterbo, Italy
| | - Luca Proietti-De-Santis
- Unit of Molecular Genetics of Aging, Department of Ecology and Biology, University of Tuscia, Viterbo, Italy
| |
Collapse
|
|
15
|
Inhibition of AKR1B10-mediated metabolism of daunorubicin as a novel off-target effect for the Bcr-Abl tyrosine kinase inhibitor dasatinib. Biochem Pharmacol 2021; 192:114710. [PMID: 34339712 DOI: 10.1016/j.bcp.2021.114710] [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] [Received: 05/06/2021] [Revised: 07/22/2021] [Accepted: 07/23/2021] [Indexed: 11/22/2022]
Abstract
Bcr-Abl tyrosine kinase inhibitors significantly improved Philadelphia chromosome-positive leukaemia therapy. Apart from Bcr-Abl kinase, imatinib, dasatinib, nilotinib, bosutinib and ponatinib are known to have additional off-target effects that might contribute to their antitumoural activities. In our study, we identified aldo-keto reductase 1B10 (AKR1B10) as a novel target for dasatinib. The enzyme AKR1B10 is upregulated in several cancers and influences the metabolism of chemotherapy drugs, including anthracyclines. AKR1B10 reduces anthracyclines to alcohol metabolites that show less antineoplastic properties and tend to accumulate in cardiac tissue. In our experiments, clinically achievable concentrations of dasatinib selectively inhibited AKR1B10 both in experiments with recombinant enzyme (Ki = 0.6 µM) and in a cellular model (IC50 = 0.5 µM). Subsequently, the ability of dasatinib to attenuate AKR1B10-mediated daunorubicin (Daun) resistance was determined in AKR1B10-overexpressing cells. We have demonstrated that dasatinib can synergize with Daun in human cancer cells and enhance its therapeutic effectiveness. Taken together, our results provide new information on how dasatinib may act beyond targeting Bcr-Abl kinase, which may help to design new chemotherapy regimens, including those with anthracyclines.
Collapse
|
|
16
|
Zhong L, Li Y, Xiong L, Wang W, Wu M, Yuan T, Yang W, Tian C, Miao Z, Wang T, Yang S. Small molecules in targeted cancer therapy: advances, challenges, and future perspectives. Signal Transduct Target Ther 2021; 6:201. [PMID: 34054126 PMCID: PMC8165101 DOI: 10.1038/s41392-021-00572-w] [Citation(s) in RCA: 823] [Impact Index Per Article: 205.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 02/23/2021] [Accepted: 03/15/2021] [Indexed: 02/07/2023] Open
Abstract
Due to the advantages in efficacy and safety compared with traditional chemotherapy drugs, targeted therapeutic drugs have become mainstream cancer treatments. Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By December 2020, 89 small-molecule targeted antitumor drugs have been approved by the US FDA and the National Medical Products Administration (NMPA) of China. Despite great progress, small-molecule targeted anti-cancer drugs still face many challenges, such as a low response rate and drug resistance. To better promote the development of targeted anti-cancer drugs, we conducted a comprehensive review of small-molecule targeted anti-cancer drugs according to the target classification. We present all the approved drugs as well as important drug candidates in clinical trials for each target, discuss the current challenges, and provide insights and perspectives for the research and development of anti-cancer drugs.
Collapse
Affiliation(s)
- Lei Zhong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China
| | - Yueshan Li
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Liang Xiong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Wenjing Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ming Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Ting Yuan
- Personalized Drug Therapy Key Laboratory of Sichuan Province, Department of Pharmacy, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, People's Republic of China
| | - Wei Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Chenyu Tian
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Zhuang Miao
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Tianqi Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China
| | - Shengyong Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People's Republic of China.
| |
Collapse
|
|
17
|
Ma XY, Wei L, Lei Z, Chen Y, Ding Z, Chen ZS. Recent progress on targeting leukemia stem cells. Drug Discov Today 2021; 26:1904-1913. [PMID: 34029689 DOI: 10.1016/j.drudis.2021.05.009] [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: 01/29/2021] [Revised: 04/14/2021] [Accepted: 05/17/2021] [Indexed: 10/21/2022]
Abstract
Leukemia is a type of malignant clonal disease of hematopoietic stem cells (HSCs). A small population of leukemic stem cells (LSCs) are responsible for the initiation, drug resistance, and relapse of leukemia. LSCs have the ability to form tumors after xenotransplantation in immunodeficient mice and appear to be common in most human leukemias. Therefore, the eradication of LSCs is an approach with the potential to improve survival or even to cure leukemia. Using recent research in the field of LSCs, we summarize the targeted therapy approaches for the removal of LSCs through surface markers including immune checkpoint molecules, pathways influencing LSC survival, or the survival microenvironment of LSCs. In addition, we introduce the survival microenvironment and survival regulation of LSCs.
Collapse
Affiliation(s)
- Xiang-Yu Ma
- School of Pharmacy, Weifang Medical University, Weifang 261053, PR China
| | - Liuya Wei
- School of Pharmacy, Weifang Medical University, Weifang 261053, PR China.
| | - Zining Lei
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY 11439, USA
| | - Yanglu Chen
- Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
| | - Zhiyong Ding
- Mills Institute for Personalized Cancer Care, Fynn Biotechnologies Ltd., Gangxing 3rd Rd, High-Tech and Innovation Zone, Jinan, Shandong 250101, PR China
| | - Zhe-Sheng Chen
- School of Pharmacy, Weifang Medical University, Weifang 261053, PR China.
| |
Collapse
|
|
18
|
Guillen A, Smallwood K, Killick DR. Molecular pathology in the cancer clinic - where are we now and where are we headed? J Small Anim Pract 2021; 62:507-520. [PMID: 33974272 DOI: 10.1111/jsap.13330] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Revised: 12/14/2020] [Accepted: 03/04/2021] [Indexed: 11/29/2022]
Abstract
Molecular pathology is a developing sub-microscopic discipline of pathology that studies the effects of molecular variations and mutations on disease processes. The ultimate goal of molecular pathology in cancer is to predict risk, facilitate diagnosis and improve prognostication based on a complete understanding of the biological impact of specific molecular variations, mutations and dysregulations. This knowledge will provide the basis for customised cancer treatment, so-called precision medicine. Rapid developments in genomics have placed this field at the forefront of clinical molecular pathology and there are already a number of well-established genetic tests available for clinical use including PCR of antigen receptor rearrangement and KIT mutational analysis. Moving beyond tests assessing a single gene, there are significant research efforts utilising genomics to predict cancer risk, forecast aggressive behaviour and identify druggable mutations and therapeutic biomarkers. Researchers are also investigating the use of circulating cells and nucleic acid for clinically useful low morbidity genomic assessments. If we are to realise the full potential of molecular pathology and precision medicine there are a number of challenges to overcome. These include developing our understanding of the underlying biology (in particular intra-tumoural heterogeneity), methodological standardisation of assays, provision of adequate infrastructure and production of novel therapeutics backed by high-quality clinical data supporting the precision medicine approach. The era of molecular pathology holds the potential to revolutionise veterinary cancer care, but its impact on clinical practice will depend upon the extent to which the inherent challenges can be overcome.
Collapse
Affiliation(s)
- A Guillen
- Department of Clinical Science and Services, Royal Veterinary College, Hawkshead Ln, Hatfield, AL9 7TA, UK
| | - K Smallwood
- Department of Small Animal Clinical Science, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Leahurst, Chester High Road, Neston, CH64 7TE, UK
| | - D R Killick
- Department of Small Animal Clinical Science, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Leahurst, Chester High Road, Neston, CH64 7TE, UK
| |
Collapse
|
|
19
|
DNA Repair Genes and Chronic Myeloid Leukemia: ERCC2 (751), XRCC1 (399), XRCC4-Intron 3, XRCC4 (-1394) Gene Polymorphisms. Mediterr J Hematol Infect Dis 2021; 13:e2021020. [PMID: 33747401 PMCID: PMC7938920 DOI: 10.4084/mjhid.2021.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 02/12/2021] [Indexed: 12/31/2022] Open
|
|
20
|
Zizioli D, Bernardi S, Varinelli M, Farina M, Mignani L, Bosio K, Finazzi D, Monti E, Polverelli N, Malagola M, Borsani E, Borsani G, Russo D. Development of BCR-ABL1 Transgenic Zebrafish Model Reproducing Chronic Myeloid Leukemia (CML) Like-Disease and Providing a New Insight into CML Mechanisms. Cells 2021; 10:cells10020445. [PMID: 33669758 PMCID: PMC7922348 DOI: 10.3390/cells10020445] [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: 12/30/2020] [Revised: 02/12/2021] [Accepted: 02/12/2021] [Indexed: 12/27/2022] Open
Abstract
Zebrafish has proven to be a versatile and reliable experimental in vivo tool to study human hematopoiesis and model hematological malignancies. Transgenic technologies enable the generation of specific leukemia types by the expression of human oncogenes under specific promoters. Using this technology, a variety of myeloid and lymphoid malignancies zebrafish models have been described. Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasia characterized by the BCR-ABL1 fusion gene, derived from the t (9;22) translocation causing the Philadelphia Chromosome (Ph). The BCR-ABL1 protein is a constitutively activated tyrosine kinas inducing the leukemogenesis and resulting in an accumulation of immature leukemic cells into bone marrow and peripheral blood. To model Ph+ CML, a transgenic zebrafish line expressing the human BCR-ABL1 was generated by the Gal4/UAS system, and then crossed with the hsp70-Gal4 transgenic line. The new line named (BCR-ABL1pUAS:CFP/hsp70-Gal4), presented altered expression of hematopoietic markers during embryonic development compared to controls and transgenic larvae showed proliferating hematopoietic cells in the caudal hematopoietic tissue (CHT). The present transgenic zebrafish would be a robust CML model and a high-throughput drug screening tool.
Collapse
Affiliation(s)
- Daniela Zizioli
- Unit of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.V.); (L.M.); (D.F.); (E.M.)
- Correspondence: daniela.zizioli@unibs; Tel.: +39-(03)-03717546
| | - Simona Bernardi
- Unit of Hematology, Department of Clinical and Experimental Sciences, University of Brescia, Bone Marrow Transplant Unit, ASST Spedali Civili, 25123 Brescia, Italy; (S.B.); (M.F.); (K.B.); (N.P.); (M.M.); (D.R.)
- Centro di Ricerca Emato-Oncologica AIL (CREA), ASST Spedali Civili, 25123 Brescia, Italy
| | - Marco Varinelli
- Unit of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.V.); (L.M.); (D.F.); (E.M.)
| | - Mirko Farina
- Unit of Hematology, Department of Clinical and Experimental Sciences, University of Brescia, Bone Marrow Transplant Unit, ASST Spedali Civili, 25123 Brescia, Italy; (S.B.); (M.F.); (K.B.); (N.P.); (M.M.); (D.R.)
| | - Luca Mignani
- Unit of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.V.); (L.M.); (D.F.); (E.M.)
| | - Katia Bosio
- Unit of Hematology, Department of Clinical and Experimental Sciences, University of Brescia, Bone Marrow Transplant Unit, ASST Spedali Civili, 25123 Brescia, Italy; (S.B.); (M.F.); (K.B.); (N.P.); (M.M.); (D.R.)
- Centro di Ricerca Emato-Oncologica AIL (CREA), ASST Spedali Civili, 25123 Brescia, Italy
| | - Dario Finazzi
- Unit of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.V.); (L.M.); (D.F.); (E.M.)
- Laboratorio Centrale Analisi Chimico-Cliniche, ASST Spedali Civili, 25123 Brescia, Italy
| | - Eugenio Monti
- Unit of Biotechnology, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy; (M.V.); (L.M.); (D.F.); (E.M.)
| | - Nicola Polverelli
- Unit of Hematology, Department of Clinical and Experimental Sciences, University of Brescia, Bone Marrow Transplant Unit, ASST Spedali Civili, 25123 Brescia, Italy; (S.B.); (M.F.); (K.B.); (N.P.); (M.M.); (D.R.)
| | - Michele Malagola
- Unit of Hematology, Department of Clinical and Experimental Sciences, University of Brescia, Bone Marrow Transplant Unit, ASST Spedali Civili, 25123 Brescia, Italy; (S.B.); (M.F.); (K.B.); (N.P.); (M.M.); (D.R.)
| | - Elisa Borsani
- Division of Anatomy and Physiopathology, Department of Clinical and Experimental Sciences, University of Brescia, 25123 Brescia, Italy;
| | - Giuseppe Borsani
- Unit of Biology and Genetic, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy;
| | - Domenico Russo
- Unit of Hematology, Department of Clinical and Experimental Sciences, University of Brescia, Bone Marrow Transplant Unit, ASST Spedali Civili, 25123 Brescia, Italy; (S.B.); (M.F.); (K.B.); (N.P.); (M.M.); (D.R.)
| |
Collapse
|
|
21
|
Means RT. Lymphoma classification: morphology to molecular. J Investig Med 2020; 68:319-320. [PMID: 31992657 DOI: 10.1136/jim-2019-001266] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2020] [Indexed: 11/04/2022]
Affiliation(s)
- Robert T Means
- Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA .,Department of Medical Education, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.,Department of Pathology, James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA
| |
Collapse
|
|
22
|
Prognostic Significance of Transcript-Type BCR - ABL1 in Chronic Myeloid Leukemia. Mediterr J Hematol Infect Dis 2020; 12:e2020062. [PMID: 32952973 PMCID: PMC7485470 DOI: 10.4084/mjhid.2020.062] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Accepted: 08/10/2020] [Indexed: 02/04/2023] Open
Abstract
Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene. In more than 95% of CML patients, the typical BCR-ABL1 transcript subtypes are e13a2 (b2a2), e14a2 (b3a2), or the simultaneous expression of both. Other less frequent transcript subtypes, such as e1a2, e2a2, e6a2, e19a2, e1a3, e13a3, and e14a3, have been sporadically reported. The main purpose of this review is to assess the possible impact of different transcripts on the response rate to tyrosine kinase inhibitors (TKIs), the achievement of stable deep molecular responses (s-DMR), the potential maintenance of treatment-free remission (TFR), and long-term outcome of CML patients treated with TKIs. According to the majority of published studies, patients with e13a2 transcript treated with imatinib have lower and slower cytogenetic and molecular responses than those with e14a2 transcript. They should be considered a high-risk group that would most benefit from frontline treatment with second-generation TKIs (2GTIKIs). Although few studies have been published, similar significant differences in response rates to 2GTKIs have been not reported. The e14a2 transcript seems to be a favorable prognostic factor for obtaining s-DMR, irrespective of the TKI received, and is also associated with a very high rate of TFR maintenance. Indeed, patients with e13a2 transcript achieve a lower rate of s-DMR and experience a higher probability of TFR failure. According to most reported data in the literature, the type of transcript does not seem to affect long-term outcomes of CML patients treated with TKIs. In TFR, the e14a2 transcript appears to be related to favorable responses. 2GTKIs as frontline therapy might be a convenient approach in patients with e13a2 transcript to achieve optimal long-term outcomes.
Collapse
|
|
23
|
Bothmer A, Gareau KW, Abdulkerim HS, Buquicchio F, Cohen L, Viswanathan R, Zuris JA, Marco E, Fernandez CA, Myer VE, Cotta-Ramusino C. Detection and Modulation of DNA Translocations During Multi-Gene Genome Editing in T Cells. CRISPR J 2020; 3:177-187. [PMID: 32584143 DOI: 10.1089/crispr.2019.0074] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Multiplexed genome editing with DNA endonucleases has broad application, including for cellular therapies, but chromosomal translocations, natural byproducts of inducing simultaneous genomic breaks, have not been explored in detail. Here we apply various CRISPR-Cas nucleases to edit the T cell receptor alpha and beta 2 microglobulin genes in human primary T cells and comprehensively evaluate the frequency and stability of the resulting translocations. A thorough translocation frequency analysis using three orthogonal methods (droplet digital PCR, unidirectional sequencing, and metaphase fluorescence in situ hybridization) yielded comparable results and an overall translocation rate of ∼7% between two simultaneous CRISPR-Cas9 induced edits. In addition, we show that chromosomal translocations can be reduced when using different nuclease combinations, or by the presence of a homologous single stranded oligo donor for multiplexed genome editing. Importantly, the two different approaches for translocation reduction are compatible with cell therapy applications.
Collapse
Affiliation(s)
- Anne Bothmer
- Editas Medicine, Cambridge, Massachusetts, USA
- Tessera Therapeutic, Cambridge, Massachusetts, USA
| | | | - Hayat S Abdulkerim
- Editas Medicine, Cambridge, Massachusetts, USA
- Third Rock NewCo, Cambridge, Massachusetts, USA
| | - Frank Buquicchio
- Editas Medicine, Cambridge, Massachusetts, USA
- Program in Immunology, Stanford University, Stanford, California, USA
- Department of Pathology, Stanford University, Stanford, California, USA
| | - Lucas Cohen
- Editas Medicine, Cambridge, Massachusetts, USA
- University of California San Diego, La Jolla, California, USA
| | | | | | | | - Cecilia A Fernandez
- Editas Medicine, Cambridge, Massachusetts, USA
- Diagon Therapeutic, Boston Massachusetts, USA
| | - Vic E Myer
- Editas Medicine, Cambridge, Massachusetts, USA
- Atlas Venture, Cambridge, Massachusetts, USA
| | - Cecilia Cotta-Ramusino
- Editas Medicine, Cambridge, Massachusetts, USA
- Tessera Therapeutic, Cambridge, Massachusetts, USA
| |
Collapse
|
|
24
|
Yuan X, Gao M, Bai J, Duan J. SVSR: A Program to Simulate Structural Variations and Generate Sequencing Reads for Multiple Platforms. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2020; 17:1082-1091. [PMID: 30334804 DOI: 10.1109/tcbb.2018.2876527] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
Structural variation accounts for a major fraction of mutations in the human genome and confers susceptibility to complex diseases. Next generation sequencing along with the rapid development of computational methods provides a cost-effective procedure to detect such variations. Simulation of structural variations and sequencing reads with real characteristics is essential for benchmarking the computational methods. Here, we develop a new program, SVSR, to simulate five types of structural variations (indels, tandem duplication, CNVs, inversions, and translocations) and SNPs for the human genome and to generate sequencing reads with features from popular platforms (Illumina, SOLiD, 454, and Ion Torrent). We adopt a selection model trained from real data to predict copy number states, starting from the first site of a particular genome to the end. Furthermore, we utilize references of microbial genomes to produce insertion fragments and design probabilistic models to imitate inversions and translocations. Moreover, we create platform-specific errors and base quality profiles to generate normal, tumor, or normal-tumor mixture reads. Experimental results show that SVSR could capture more features that are realistic and generate datasets with satisfactory quality scores. SVSR is able to evaluate the performance of structural variation detection methods and guide the development of new computational methods.
Collapse
|
|
25
|
Hamid AB, Petreaca RC. Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells. Cancers (Basel) 2020; 12:cancers12040927. [PMID: 32283832 PMCID: PMC7226513 DOI: 10.3390/cancers12040927] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Revised: 04/05/2020] [Accepted: 04/07/2020] [Indexed: 12/14/2022] Open
Abstract
Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.
Collapse
|
|
26
|
Chien SH, Liu HM, Chen PM, Ko PS, Lin JS, Chen YJ, Lee LH, Hsiao LT, Chiou TJ, Gau JP, Yang MH, Liu CY. The landscape of BCR-ABL mutations in patients with Philadelphia chromosome-positive leukaemias in the era of second-generation tyrosine kinase inhibitors. Hematol Oncol 2020; 38:390-398. [PMID: 32011024 DOI: 10.1002/hon.2721] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 08/24/2019] [Accepted: 01/12/2020] [Indexed: 11/09/2022]
Abstract
BCR-ABL mutations are associated with resistance to tyrosine kinase inhibitors (TKIs) in Philadelphia chromosome-positive leukaemia. The emergence of these mutations in the era of second-generation TKIs, such as dasatinib and nilotinib, remains an evolving field. We conducted a retrospective study to quantitatively characterize the BCR-ABL transcript and mutation status during treatment with first-generation and second-generation TKI therapies. BCR-ABL mutations were detected by direct sequencing for patients with Philadelphia chromosome-positive leukaemia receiving TKI therapies. The efficacy of TKI therapy was quantitatively assessed by calculating the log reduction of BCR-ABL transcripts, which was measured using real-time quantitative polymerase chain reaction. Fisher's exact test was performed to analyse the associations of log reduction <3 and mutation status. We found 35 patients harbouring 55 mutations of 43 different types, of which 30% occurred in patients receiving imatinib, 27% in nilotinib, and 43% in dasatinib. We found a novel germline mutation, N336 N (AAC➔AAT), and two novel frameshift mutations, Asn358Thr fs*14 and Gly251Ala fs*16. T315I was the most common missense mutation, followed by V299L and F317L. Intron 8 35-bp insertion was the most frequent frameshift mutation. Both missense and multiple BCR-ABL mutations were significantly associated with worse molecular response compared with the molecular response of patients without mutation. Missense mutations, rather than frameshift, were associated with less log reduction, while the T315I, F317L, and T315A mutations were significantly correlated with poor log reduction. Collectively, amino acid substitutions at T315I, F317L, and T315A accounted for the majority of missense mutations and the loss of major molecular response. Mutation analysis is essential for patients receiving TKI therapy who exhibit an unfavourable response. The present study provided a landscape of BCR-ABL mutations in the era of second-generation TKIs.
Collapse
Affiliation(s)
- Sheng-Hsuan Chien
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Hsueng-Mei Liu
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Po-Ming Chen
- Department of Food and Science and biotechnology, National Chung Hsing University, Taichung, Taiwan
| | - Po-Shen Ko
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Jeong-Shi Lin
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Ying-Ju Chen
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Li-Hsuan Lee
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Liang-Tsai Hsiao
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Tzeon-Jye Chiou
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan
| | - Jyh-Pyng Gau
- Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Muh-Hwa Yang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Chun-Yu Liu
- Division of Transfusion Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.,Faculty of Medicine, National Yang-Ming University, Taipei, Taiwan.,Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan
| |
Collapse
|
|
27
|
Abstract
The use of an acetylene (ethynyl) group in medicinal chemistry coincides with the launch of the Journal of Medicinal Chemistry in 1959. Since then, the acetylene group has been broadly exploited in drug discovery and development. As a result, it has become recognized as a privileged structural feature for targeting a wide range of therapeutic target proteins, including MAO, tyrosine kinases, BACE1, steroid receptors, mGlu5 receptors, FFA1/GPR40, and HIV-1 RT. Furthermore, a terminal alkyne functionality is frequently introduced in chemical biology probes as a click handle to identify molecular targets and to assess target engagement. This Perspective is divided into three parts encompassing: (1) the physicochemical properties of the ethynyl group, (2) the advantages and disadvantages of the ethynyl group in medicinal chemistry, and (3) the impact of the ethynyl group on chemical biology approaches.
Collapse
Affiliation(s)
- Tanaji T Talele
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, New York 11439, United States
| |
Collapse
|
|
28
|
Jiao W, Atwal G, Polak P, Karlic R, Cuppen E, Danyi A, de Ridder J, van Herpen C, Lolkema MP, Steeghs N, Getz G, Morris QD, Stein LD. A deep learning system accurately classifies primary and metastatic cancers using passenger mutation patterns. Nat Commun 2020; 11:728. [PMID: 32024849 PMCID: PMC7002586 DOI: 10.1038/s41467-019-13825-8] [Citation(s) in RCA: 118] [Impact Index Per Article: 23.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 11/26/2019] [Indexed: 12/14/2022] Open
Abstract
In cancer, the primary tumour's organ of origin and histopathology are the strongest determinants of its clinical behaviour, but in 3% of cases a patient presents with a metastatic tumour and no obvious primary. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we train a deep learning classifier to predict cancer type based on patterns of somatic passenger mutations detected in whole genome sequencing (WGS) of 2606 tumours representing 24 common cancer types produced by the PCAWG Consortium. Our classifier achieves an accuracy of 91% on held-out tumor samples and 88% and 83% respectively on independent primary and metastatic samples, roughly double the accuracy of trained pathologists when presented with a metastatic tumour without knowledge of the primary. Surprisingly, adding information on driver mutations reduced accuracy. Our results have clinical applicability, underscore how patterns of somatic passenger mutations encode the state of the cell of origin, and can inform future strategies to detect the source of circulating tumour DNA.
Collapse
Affiliation(s)
- Wei Jiao
- Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Gurnit Atwal
- Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
- Vector Institute, Toronto, ON, Canada
| | - Paz Polak
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, 15 1425 Madison Ave., New York, NY, USA
| | - Rosa Karlic
- Bioinformatics Group, Division of Molecular Biology, Department of Biology, Faculty of Science, University of Zagreb, Horvatovac 102a, Zagreb, Croatia
| | - Edwin Cuppen
- Hartwig Medical Foundation, Science Park 408, Amsterdam, The Netherlands
- Center for Molecular Medicine and Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Alexandra Danyi
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Jeroen de Ridder
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Martijn P Lolkema
- Department of Medical Oncology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Dr. Molewaterplein 40, 3015 GD, Rotterdam, The Netherlands
| | - Neeltje Steeghs
- Department of Medical Oncology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands
| | - Gad Getz
- Broad Institute of MIT and Harvard, Cambridge, MA, USA
- Harvard Medical School, Boston, MA, USA
- Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA
- Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
| | - Quaid D Morris
- Vector Institute, Toronto, ON, Canada
- University of Toronto, Toronto, ON, Canada
| | - Lincoln D Stein
- Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada.
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
| |
Collapse
|
|
29
|
Liu J, Pei J, Lai L. A combined computational and experimental strategy identifies mutations conferring resistance to drugs targeting the BCR-ABL fusion protein. Commun Biol 2020; 3:18. [PMID: 31925328 PMCID: PMC6952392 DOI: 10.1038/s42003-019-0743-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 12/17/2019] [Indexed: 12/25/2022] Open
Abstract
Drug resistance is of increasing concern, especially during the treatments of infectious diseases and cancer. To accelerate the drug discovery process in combating issues of drug resistance, here we developed a computational and experimental strategy to predict drug resistance mutations. Using BCR-ABL as a case study, we successfully recaptured the clinically observed mutations that confer resistance imatinib, nilotinib, dasatinib, bosutinib, and ponatinib. We then experimentally tested the predicted mutants in vitro. We found that although all mutants showed weakened binding strength as expected, the binding constants alone were not a good indicator of drug resistance. Instead, the half-maximal inhibitory concentration (IC50) was shown to be a good indicator of the incidence of the predicted mutations, together with change in catalytic efficacy. Our suggested strategy for predicting drug-resistance mutations includes the computational prediction and in vitro selection of mutants with increased IC50 values beyond the drug safety window.
Collapse
Affiliation(s)
- Jinxin Liu
- The PTN Graduate Program, College of Life Sciences, Peking University, Beijing, 100871, P. R. China
| | - Jianfeng Pei
- Center for Quantitative Biology, AAIS, Peking University, Beijing, 100871, P. R. China.
| | - Luhua Lai
- Center for Quantitative Biology, AAIS, Peking University, Beijing, 100871, P. R. China.
- BNLMS, Peking-Tsinghua Center for Life Sciences at College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, P. R. China.
| |
Collapse
|
|
30
|
Co-Operation between Aneuploidy and Metabolic Changes in Driving Tumorigenesis. Int J Mol Sci 2019; 20:ijms20184611. [PMID: 31540349 PMCID: PMC6770258 DOI: 10.3390/ijms20184611] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Revised: 09/05/2019] [Accepted: 09/17/2019] [Indexed: 12/11/2022] Open
Abstract
Alterations from the normal set of chromosomes are extremely common as cells progress toward tumourigenesis. Similarly, we expect to see disruption of normal cellular metabolism, particularly in the use of glucose. In this review, we discuss the connections between these two processes: how chromosomal aberrations lead to metabolic disruption, and vice versa. Both processes typically result in the production of elevated levels of reactive oxygen species, so we particularly focus on their role in mediating oncogenic changes.
Collapse
|
|
31
|
Wang H, Wang H, Jia Y, Sun R, Hong W, Zhang M, Li Z. Visual Detection of Fusion Genes by Ligation-Triggered Isothermal Exponential Amplification: A Point-of-Care Testing Method for Highly Specific and Sensitive Quantitation of Fusion Genes with a Smartphone. Anal Chem 2019; 91:12428-12434. [PMID: 31464423 DOI: 10.1021/acs.analchem.9b03061] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Fusion genes, playing a causal role in human tumorigenesis and developments, are deemed as gold standard molecular biomarkers in cancer diagnosis, therapy, and prognosis. A rapid, robust, and sensitive method of detection of fusion genes for point-of-care (POC) diagnosis is urgently needed. Here, taking the advantages of the superior specificity of the ligation reaction and the highly amplified efficiency of isothermal exponential amplification with a pH indicator, we developed a colorimetric method for visual detection of fusion genes with high sensitivity and specificity by the naked eye. More importantly, we first found that fusion genes can be accurately quantified in a wide dynamic range (2 zmol to 2 fmol) by an open-source app with a smartphone-assisted RGB (red, green, and blue value) reading mode. The proposed method for Visual detection of Fusion genes by Ligation-triggered Isothermal Exponential Amplification is termed Vis-Fusion LIEXA. We have demonstrated that the Vis-Fusion LIEXA is a practical and reliable method for accurate quantitative detection of the fusion gene in a complex biological sample at zmol level in 40 min only with a smartphone, thereby providing a user-friendly and point-of-care testing (POCT) tool for molecular diagnostics.
Collapse
Affiliation(s)
- Hui Wang
- School of Chemistry and Biological Engineering , University of Science and Technology Beijing , 30 Xueyuan Road , Haidian District, Beijing 100083 , P. R. China
| | - Honghong Wang
- School of Chemistry and Biological Engineering , University of Science and Technology Beijing , 30 Xueyuan Road , Haidian District, Beijing 100083 , P. R. China
| | - Yuting Jia
- School of Chemistry and Biological Engineering , University of Science and Technology Beijing , 30 Xueyuan Road , Haidian District, Beijing 100083 , P. R. China
| | - Ruyan Sun
- School of Chemistry and Biological Engineering , University of Science and Technology Beijing , 30 Xueyuan Road , Haidian District, Beijing 100083 , P. R. China
| | - Weixiang Hong
- School of Chemistry and Biological Engineering , University of Science and Technology Beijing , 30 Xueyuan Road , Haidian District, Beijing 100083 , P. R. China
| | - Mai Zhang
- School of Chemistry and Biological Engineering , University of Science and Technology Beijing , 30 Xueyuan Road , Haidian District, Beijing 100083 , P. R. China
| | - Zhengping Li
- School of Chemistry and Biological Engineering , University of Science and Technology Beijing , 30 Xueyuan Road , Haidian District, Beijing 100083 , P. R. China
| |
Collapse
|
|
32
|
Yin B, Fang DM, Zhou XL, Gao F. Natural products as important tyrosine kinase inhibitors. Eur J Med Chem 2019; 182:111664. [PMID: 31494475 DOI: 10.1016/j.ejmech.2019.111664] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2019] [Revised: 07/13/2019] [Accepted: 08/29/2019] [Indexed: 12/27/2022]
Abstract
As an important source of drugs, natural products play an important role in the discovery and development of new drugs. More than 60% of anti-tumor drugs are closely related to natural products. At the same time, as the main cause of tumors, the abnormal activity of tyrosine kinase has become an important target for clinical treatment. Although, small molecule targeted drugs dominate the cancer treatment. Natural active products are driving the development of new tyrosine kinase inhibitors with their unique mode of action and molecular structure diversity. Obtaining new chemical entities with tyrosine kinase inhibitory activity from natural active products will bring new breakthroughs in the research of anticancer drugs. In this paper, different tyrosine kinases are mainly classified as targets, and natural products and derivatives which have been found to inhibit tyrosine kinase activity have been described. It is hoped that by analyzing the different aspects of the source, structural characteristics, mechanism of action and biological activity of these natural products, we will find new members that can be developed into drugs and promote the development of anti-tumor drugs.
Collapse
Affiliation(s)
- Bo Yin
- Laboratory of Chemistry and Biodiversity, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China
| | - Dong-Mei Fang
- Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu, 610041, PR China
| | - Xian-Li Zhou
- Laboratory of Chemistry and Biodiversity, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China
| | - Feng Gao
- Laboratory of Chemistry and Biodiversity, School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, PR China.
| |
Collapse
|
|
33
|
Lei H, Tu Y, Yang L, Jin J, Luo H, Xu H, Kang J, Zhou L, Wu Y. Quinacrine Depletes BCR-ABL and Suppresses Ph-Positive Leukemia Cells. Cancer Invest 2019; 37:242-252. [PMID: 31296070 DOI: 10.1080/07357907.2019.1630633] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Drug resistance to TKIs and the existance of CML leukemia stem cells is an urgent problem. In this study, we demonstrate that quinacrine (QC) induces apoptosis in BCR-ABL positive CML and acute lymphoblastic leukemia (ALL) cells. Interestingly, QC inhibits the colony formation of primary CD34+ progenitor/stem leukemia cells from CML patients. QC targets RNA polymerase I, which produces ribosomal (r)RNA, involving in protein translation process. Also, QC treatment prolongs CML-like mice survival and inhibits K562 tumor growth in vivo. In conclusion, we demonstrate that QC depletes BCR-ABL protein and suppresses Ph-positive leukemia cells in vitro and in vivo.
Collapse
Affiliation(s)
- Hu Lei
- a Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Yaoyao Tu
- a Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Li Yang
- a Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Jin Jin
- a Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Hao Luo
- a Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Hanzhang Xu
- a Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Jingwu Kang
- b State Key Laboratory of Bioorganic and Natural Products Chemistry, Chinese Academy of Sciences , Shanghai , China
| | - Li Zhou
- c Department of Hematology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| | - Yingli Wu
- a Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Hongqiao International Institute of Medicine, Shanghai Tongren Hospital, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine , Shanghai , China
| |
Collapse
|
|
34
|
Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo. Ann Hematol 2019; 98:1905-1918. [PMID: 31104089 DOI: 10.1007/s00277-019-03713-y] [Citation(s) in RCA: 68] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 05/05/2019] [Indexed: 01/04/2023]
Abstract
Efficient and safe delivery of siRNA in vivo is the biggest roadblock to clinical translation of RNA interference (RNAi)-based therapeutics. To date, lipid nanoparticles (LNPs) have shown efficient delivery of siRNA to the liver; however, delivery to other organs, especially hematopoietic tissues still remains a challenge. We developed DLin-MC3-DMA lipid-based LNP-siRNA formulations for systemic delivery against a driver oncogene to target human chronic myeloid leukemia (CML) cells in vivo. A microfluidic mixing technology was used to obtain reproducible ionizable cationic LNPs loaded with siRNA molecules targeting the BCR-ABL fusion oncogene found in CML. We show a highly efficient and non-toxic delivery of siRNA in vitro and in vivo with nearly 100% uptake of LNP-siRNA formulations in bone marrow of a leukemic model. By targeting the BCR-ABL fusion oncogene, we show a reduction of leukemic burden in our myeloid leukemia mouse model and demonstrate reduced disease burden in mice treated with LNP-BCR-ABL siRNA as compared with LNP-CTRL siRNA. Our study provides proof-of-principle that fusion oncogene specific RNAi therapeutics can be exploited against leukemic cells and promise novel treatment options for leukemia patients.
Collapse
|
|
35
|
Prosurvival kinase PIM2 is a therapeutic target for eradication of chronic myeloid leukemia stem cells. Proc Natl Acad Sci U S A 2019; 116:10482-10487. [PMID: 31068472 DOI: 10.1073/pnas.1903550116] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
A major obstacle to curing chronic myeloid leukemia (CML) is the intrinsic resistance of CML stem cells (CMLSCs) to the drug imatinib mesylate (IM). Prosurvival genes that are preferentially expressed in CMLSCs compared with normal hematopoietic stem cells (HSCs) represent potential therapeutic targets for selectively eradicating CMLSCs. However, the discovery of such preferentially expressed genes has been hampered by the inability to completely separate CMLSCs from HSCs, which display a very similar set of surface markers. To overcome this challenge, and to minimize confounding effects of individual differences in gene expression profiles, we performed single-cell RNA-seq on CMLSCs and HSCs that were isolated from the same patient and distinguished based on the presence or absence of BCR-ABL. Among genes preferentially expressed in CMLSCs is PIM2, which encodes a prosurvival serine-threonine kinase that phosphorylates and inhibits the proapoptotic protein BAD. We show that IM resistance of CMLSCs is due, at least in part, to maintenance of BAD phosphorylation by PIM2. We find that in CMLSCs, PIM2 expression is promoted by both a BCR-ABL-dependent (IM-sensitive) STAT5-mediated pathway and a BCR-ABL-independent (IM-resistant) STAT4-mediated pathway. Combined treatment with IM and a PIM inhibitor synergistically increases apoptosis of CMLSCs, suppresses colony formation, and significantly prolongs survival in a mouse CML model, with a negligible effect on HSCs. Our results reveal a therapeutically targetable mechanism of IM resistance in CMLSCs. The experimental approach that we describe can be generally applied to other malignancies that harbor oncogenic fusion proteins or other characteristic genetic markers.
Collapse
|
|
36
|
Leeman-Neill RJ, Swerdlow SH, Burnes CL, Melan MA, Nikiforova MN, Surti U, Aggarwal N. Low-level BCR-ABL1 transcripts in individuals without overt hematologic malignancy. Leuk Res 2019; 81:98-101. [PMID: 31047698 DOI: 10.1016/j.leukres.2019.04.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Revised: 04/18/2019] [Accepted: 04/21/2019] [Indexed: 11/16/2022]
Affiliation(s)
- Rebecca J Leeman-Neill
- University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Steven H Swerdlow
- University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Catherine L Burnes
- University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Melissa A Melan
- University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Marina N Nikiforova
- University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Urvashi Surti
- University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, United States
| | - Nidhi Aggarwal
- University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center, Pittsburgh, PA, United States.
| |
Collapse
|
|
37
|
Molecular dynamics investigation on the Asciminib resistance mechanism of I502L and V468F mutations in BCR-ABL. J Mol Graph Model 2019; 89:242-249. [PMID: 30927708 DOI: 10.1016/j.jmgm.2019.03.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 02/23/2019] [Accepted: 03/18/2019] [Indexed: 01/29/2023]
Abstract
Asciminib, a highly selective non-ATP competitive inhibitor of BCR-ABL, has demonstrated to be a promising drug for patients with chronic myeloid leukemia. It is a pity that two resistant mutations (I502L and V468F) have been found during the clinical trial, which is a challenge for the curative effect of Asciminib. In this study, molecular dynamics simulations and molecular mechanics generalized Born surface area (MM-GB/SA) calculations were performed to investigate the molecular mechanism of Asciminib resistance induced by the two mutants. The obtained results indicate that the mutations have adversely influence on the binding of Asciminib to BCR-ABL, as the nonpolar contributions decline in the two mutants. In addition, I502L mutation causes α-helix I' (αI') to shift away from the helical bundle composed of αE, αF, and αH, making the distance between αI' and Asciminib increased. For V468F mutant, the side chain of Phe468 occupies the bottom of the myristoyl pocket (MP), which drives Asciminib to shift toward the outside of MP. Our results provide the molecular insights of Asciminib resistance mechanism in BCR-ABL mutants, which may help the design of novel inhibitors.
Collapse
|
|
38
|
Nomura S, Ito T, Satake A, Ishii K. Assessment of soluble cytotoxic T lymphocyte-associated antigen-4, transforming growth factor β 1, and platelet-derived microparticles during dasatinib therapy for patients with chronic myelogenous leukemia. J Blood Med 2018; 10:1-8. [PMID: 30588140 PMCID: PMC6305157 DOI: 10.2147/jbm.s187005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND The outcome for chronic myelogenous leukemia (CML) patients presented in the chronic phase has changed dramatically since the introduction of tyrosine kinase inhibitor (TKI) therapy. Notably, an increased incidence of large granular lymphocytes (LGLs), which is related to immunological conditions, appears to be predictive of a favorable outcome for dasatinib therapy. We therefore examined the immunological characteristics of CML patients during dasatinib therapy by determining the plasma concentrations of five different biomarkers. METHODS The plasma levels of biomarkers, specifically interleukin-6, platelet-derived microparticles (PDMPs), soluble vascular cell adhesion molecule 1 (sVCAM-1), transforming growth factor (TGF) β1, and soluble cytotoxic T lymphocyte-associated antigen-4 (sCTLA-4), were measured by ELISA at baseline and after 2 and 6 months of TKI treatment. The incidence of LGLs was estimated by microscopic examination. RESULTS The levels of PDMPs, sVCAM-1, and TGFβ1 were significantly elevated in patients with CML. Dasatinib treatment was associated with a significant reduction in the levels of these markers and with an increased incidence of LGLs compared with imatinib or nilotinib treatment. In addition, an increased incidence of LGLs was significantly correlated with a decreased sCTLA-4 level during dasatinib therapy. CONCLUSION The assessment of the levels of specific biomarkers may be beneficial to understand the immunological conditions of patients with CML during dasatinib treatment.
Collapse
Affiliation(s)
- Shosaku Nomura
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan,
| | - Tomoki Ito
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan,
| | - Atsushi Satake
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan,
| | - Kazuyoshi Ishii
- First Department of Internal Medicine, Kansai Medical University, Hirakata, Osaka, Japan,
| |
Collapse
|
|
39
|
Shu Y, Yang W, Zhang X, Xu X. Recurrent chronic myeloid leukemia with t (9;22;16) (q34; q11; p13) treated by nilotinib: A case report. Medicine (Baltimore) 2018; 97:e12875. [PMID: 30335005 PMCID: PMC6211866 DOI: 10.1097/md.0000000000012875] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
RATIONALE Variant Philadelphia chromosome translocations involving chromosomes other than chromosomes 9 and 22 have been reported in 5% to 10% of patients with chronic myeloid leukemia (CML). Here, a case of CML with a t (9, 22, 16) (q34; q11; p13) translocation, which has never been described, is reported. PATIENT CONCERNS A 59-year-old female with dry cough, referred to our hospital, exhibited hepatosplenomegaly, high basophil count, and high platelet count at admission without any other known chronic diseases. DIAGNOSES The patient was diagnosed with CML with the translocation t (9;22;16) (q34; q11; p13). The patient was treated with imatinib, a first-generation tyrosine kinase inhibitor (TKI), discontinuously, achieving a complete hematological response for 7 years. Since November 8, 2017, the patient had recurrent fever, and her platelet count rose to 1422 × 10/L. Subsequently, the E279K mutation in the BCR-ABL kinase region was detected. OUTCOMES According to a previous report, this mutation confers sensitivity to nilotinib, a second-generation TKI. In the end, the patient received treatment with nilotinib and showed a complete hematological response. LESSONS The present study reports a rare case of CML with Ph chromosome and a t (9;22;16) (q34; q11; p13) translocation. For such cases about CML with variant Philadelphia chromosome translocations or BCR-ABL kinase region mutation, TKI may still be valuable.
Collapse
MESH Headings
- Antineoplastic Agents/administration & dosage
- Chromosomes, Human, 16-18/genetics
- Chromosomes, Human, Pair 22/genetics
- Chromosomes, Human, Pair 9/genetics
- Female
- Humans
- Imatinib Mesylate/administration & dosage
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics
- Middle Aged
- Mutation
- Neoplasm Recurrence, Local/drug therapy
- Neoplasm Recurrence, Local/genetics
- Philadelphia Chromosome
- Pyrimidines/administration & dosage
- Translocation, Genetic/genetics
Collapse
|
|
40
|
Papadopoulos N, Lennartsson J. The PDGF/PDGFR pathway as a drug target. Mol Aspects Med 2018; 62:75-88. [DOI: 10.1016/j.mam.2017.11.007] [Citation(s) in RCA: 100] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 11/10/2017] [Indexed: 02/07/2023]
|
|
41
|
Zhou C, Liu L, Zhuang J, Wei J, Zhang T, Gao C, Liu C, Li H, Si H, Sun C. A Systems Biology-Based Approach to Uncovering Molecular Mechanisms Underlying Effects of Traditional Chinese Medicine Qingdai in Chronic Myelogenous Leukemia, Involving Integration of Network Pharmacology and Molecular Docking Technology. Med Sci Monit 2018; 24:4305-4316. [PMID: 29934492 PMCID: PMC6049014 DOI: 10.12659/msm.908104] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Background The method of multiple targets overall control is increasingly used to predict the main active ingredient and potential target group of Chinese traditional medicines and to determine the mechanisms involved in their curative effects. Qingdai is the main traditional Chinese medicine used in the treatment of chronic myelogenous leukemia (CML), but the complex active ingredients and antitumor targets in treatment of CML have not been clearly defined in previous studies. Material/Methods We constructed a protein-protein interaction network diagram of CML with 638 nodes (proteins) and 1830 edges, based on the biological function of chronic myelocytic leukemia by use of Cytoscape, and we determined 19 key gene nodes in the CML molecule by network topological properties analysis in a data bank. Then, we used the Surflex-dock plugin in SYBYL7.3 docking and acquired the protein crystal structures of key genes involved in CML from the chemical composition of the traditional Chinese medicine Qingdai with key proteins in CML networks. Results According to the score and the spatial structure, the pharmacodynamically active ingredients of Qingdai are Isdirubin, Isoindigo, N-phenyl-2-naphthylamine, and Isatin, among which Isdirubin is the most important. We further screened the most effective activity key protein structures of CML to find the best pharmacodynamically active ingredients of Qingdai, according to the binding interactions of the inhibitors at the catalytic site performed in best docking combinations. Conclusions The results suggest that Isdirubin plays a role in resistance to CML by altering the expressions of PIK3CA, MYC, JAK2, and TP53 target proteins. Network pharmacology and molecular docking technology can be used to search for possible reactive molecules in traditional chinese medicines (TCM) and to elucidate their molecular mechanisms.
Collapse
Affiliation(s)
- Chao Zhou
- Cancer Center, WeiFang Traditional Chinese Hospital, Weifang, Shandong, China (mainland)
| | - LiJuan Liu
- Cancer Center, WeiFang Traditional Chinese Hospital, Weifang, Shandong, China (mainland)
| | - Jing Zhuang
- Cancer Center, WeiFang Traditional Chinese Hospital, Weifang, Shandong, China (mainland)
| | - JunYu Wei
- Cancer Center, WeiFang Traditional Chinese Hospital, Weifang, Shandong, China (mainland)
| | - TingTing Zhang
- Clinical Institute, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (mainland)
| | - ChunDi Gao
- Clinical Institute, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (mainland)
| | - Cun Liu
- Clinical Institute, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (mainland)
| | - HuaYao Li
- Clinical Institute, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, China (mainland)
| | - HongZong Si
- Department of Public Health, Qingdao University, Qingdao, Shandong, China (mainland)
| | - ChangGang Sun
- Department of Oncology, Affiliated Hospital of Weifang Medical University, Weifang, Shandong, China (mainland)
| |
Collapse
|
|
42
|
García-Tuñón I, Hernández-Sánchez M, Ordoñez JL, Alonso-Pérez V, Álamo-Quijada M, Benito R, Guerrero C, Hernández-Rivas JM, Sánchez-Martín M. The CRISPR/Cas9 system efficiently reverts the tumorigenic ability of BCR/ABL in vitro and in a xenograft model of chronic myeloid leukemia. Oncotarget 2018; 8:26027-26040. [PMID: 28212528 PMCID: PMC5432235 DOI: 10.18632/oncotarget.15215] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Accepted: 01/27/2017] [Indexed: 11/25/2022] Open
Abstract
CRISPR/Cas9 technology was used to abrogate p210 oncoprotein expression in the Boff-p210 cell line, a pro-B line derived from interlukin-3-dependent Baf/3, that shows IL-3-independence arising from the constitutive expression of BCR-ABL p210. Using this approach, pools of Boff-p210-edited cells and single edited cell-derived clones were obtained and functionally studied in vitro. The loss of p210 expression in Boff-p210 cells resulted in the loss of ability to grow in the absence of IL-3, as the Baf/3 parental line, showing significantly increased apoptosis levels. Notably, in a single edited cell-derived clone carrying a frame-shift mutation that prevents p210 oncoprotein expression, the effects were even more drastic, resulting in cell death. These edited cells were injected subcutaneously in immunosuppressed mice and tumor growth was followed for three weeks. BCR/ABL-edited cells developed smaller tumors than those originating from unedited Boff-p210 parental cells. Interestingly, the single edited cell-derived clone was unable to develop tumors, similar to what is observed with the parental Baf/3 cell line. CRISPR/Cas9 genomic editing technology allows the ablation of the BCR/ABL fusion gene, causing an absence of oncoprotein expression, and blocking its tumorigenic effects in vitro and in the in vivo xenograft model of CML. The future application of this approach in in vivo models of CML will allow us to more accurately assess the value of CRISPR/Cas9 technology as a new therapeutic tool that overcomes resistance to the usual treatments for CML patients.
Collapse
Affiliation(s)
- Ignacio García-Tuñón
- Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
| | - María Hernández-Sánchez
- Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
| | - José Luis Ordoñez
- Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
| | - Veronica Alonso-Pérez
- Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
| | - Miguel Álamo-Quijada
- Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
| | - Rocio Benito
- Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain
| | - Carmen Guerrero
- IBSAL, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain.,Instituto Biología Molecular y Celular del Cáncer (USAL/CSIC), Salamanca, Spain.,Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
| | - Jesús María Hernández-Rivas
- Unidad de Diagnóstico Molecular y Celular del Cáncer, Centro de Investigación del Cáncer-IBMCC (USAL-CSIC), Salamanca, Spain.,IBSAL, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain.,Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain
| | - Manuel Sánchez-Martín
- IBSAL, Instituto de Investigación Biomédica de Salamanca, Salamanca, Spain.,Servicio de Transgénesis, Nucleus, Universidad de Salamanca, Salamanca, Spain.,Departamento de Medicina, Universidad de Salamanca, Salamanca, Spain
| |
Collapse
|
|
43
|
Malouf C, Ottersbach K. Molecular processes involved in B cell acute lymphoblastic leukaemia. Cell Mol Life Sci 2018; 75:417-446. [PMID: 28819864 PMCID: PMC5765206 DOI: 10.1007/s00018-017-2620-z] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Revised: 08/01/2017] [Accepted: 08/04/2017] [Indexed: 12/19/2022]
Abstract
B cell leukaemia is one of the most frequent malignancies in the paediatric population, but also affects a significant proportion of adults in developed countries. The majority of infant and paediatric cases initiate the process of leukaemogenesis during foetal development (in utero) through the formation of a chromosomal translocation or the acquisition/deletion of genetic material (hyperdiploidy or hypodiploidy, respectively). This first genetic insult is the major determinant for the prognosis and therapeutic outcome of patients. B cell leukaemia in adults displays similar molecular features as its paediatric counterpart. However, since this disease is highly represented in the infant and paediatric population, this review will focus on this demographic group and summarise the biological, clinical and epidemiological knowledge on B cell acute lymphoblastic leukaemia of four well characterised subtypes: t(4;11) MLL-AF4, t(12;21) ETV6-RUNX1, t(1;19) E2A-PBX1 and t(9;22) BCR-ABL1.
Collapse
Affiliation(s)
- Camille Malouf
- MRC Centre for Regenerative Medicine, The University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK
| | - Katrin Ottersbach
- MRC Centre for Regenerative Medicine, The University of Edinburgh, 5 Little France Drive, Edinburgh, EH16 4UU, UK.
| |
Collapse
|
|
44
|
Myelodysplasia and Mast Cell Leukemia with t(9;22). Case Rep Oncol Med 2018; 2017:9249302. [PMID: 29318069 PMCID: PMC5727626 DOI: 10.1155/2017/9249302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2017] [Revised: 10/13/2017] [Accepted: 10/25/2017] [Indexed: 12/24/2022] Open
Abstract
Introduction Mast cell leukemia (MCL) is a rare variant of systemic mastocytosis. Most cases of mast cell leukemia do not have cytogenics performed. Furthermore, there is no consistent chromosomal abnormality identified in MCL. This is the first reported case of MCL with a (9;22) translocation. Case Report An 80-year-old female presented with pancytopenia and was diagnosed with MDS. Over time, she required hospitalizations for platelet transfusions with increased frequency. She developed fatigue and weakness along with gastrointestinal symptoms. On exam, she had diffuse abdominal tenderness and a maculopapular rash. Her lab results revealed a new basophilia. A bone marrow biopsy showed 100% cellularity with many aggregates of mast cells. Chromosomal analysis showed t(9;22) with confirmed BCR/ABL1 fusion by fluorescence in situ hybridization (FISH). Discussion MCL has a poor prognosis due to the aggressive nature of the disease and ineffective therapies. Translocation (9;22) is known to be associated with MDS transformations to acute leukemia; however, this translocation has never been reported in MCL. Further research on the relationship between t(9;22) and MCL could lead to development of improved therapeutic options.
Collapse
|
|
45
|
Corrente F, Bellesi S, Metafuni E, Puggioni PL, Marietti S, Ciminello AM, Za T, Sorà F, Fianchi L, Sica S, De Stefano V, Chiusolo P. Role of flow-cytometric immunophenotyping in prediction ofBCR/ABL1gene rearrangement in adult B-cell acute lymphoblastic leukemia. CYTOMETRY PART B-CLINICAL CYTOMETRY 2017; 94:468-476. [DOI: 10.1002/cyto.b.21605] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/24/2017] [Revised: 11/29/2017] [Accepted: 12/05/2017] [Indexed: 11/06/2022]
Affiliation(s)
- Francesco Corrente
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Silvia Bellesi
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Elisabetta Metafuni
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Pier Luigi Puggioni
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Sara Marietti
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Angela Maria Ciminello
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Tommaso Za
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Federica Sorà
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Luana Fianchi
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Simona Sica
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Valerio De Stefano
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| | - Patrizia Chiusolo
- Institute of Hematology, Catholic University of Sacred Heart; Largo A. Gemelli 8, Rome, 00168 Italy
| |
Collapse
|
|
46
|
Nutlin-3 plus tanshinone IIA exhibits synergetic anti-leukemia effect with imatinib by reactivating p53 and inhibiting the AKT/mTOR pathway in Ph+ ALL. Biochem J 2017; 474:4153-4170. [PMID: 29046392 DOI: 10.1042/bcj20170386] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Revised: 10/09/2017] [Accepted: 10/16/2017] [Indexed: 02/05/2023]
Abstract
Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) is triggered by BCR/ABL kinase. Recent efforts focused on the development of more potent tyrosine kinase inhibitors (TKIs) that also inhibit mutant tyrosine kinases such as nilotinib and dasatinib. Although major advances in the treatment of this aggressive disease with potent inhibitors of the BCR/ABL kinases, patients in remission frequently relapse due to drug resistance possibly mediated, at least in part, by compensatory activation of growth-signaling pathways and protective feedback signaling of leukemia cells in response to TKI treatment. Continuous activation of AKT/mTOR signaling and inactivation of p53 pathway were two mechanisms of TKI resistance. Here, we reported that nutlin-3 plus tanshinone IIA significantly potentiated the cytotoxic and apoptotic induction effects of imatinib by down-regulation of the AKT/mTOR pathway and reactivating the p53 pathway deeply in Ph+ ALL cell line. In primary samples from Ph+ ALL patients, nutlin-3 plus tanshinone IIA also exhibited synergetic cytotoxic effects with imatinib. Of note, three samples from Ph+ ALL patients harboring T315I mutation also showed sensitivity to the combined treatment of imatinib, nutlin-3 plus tanshinone IIA. In Ph+ ALL mouse models, imatinib combined with nutlin-3 plus tanshinone IIA also exhibited synergetic effects on reduction in leukemia burden. These results demonstrated that nutlin-3 plus tanshinone IIA combined TKI might be a promising treatment strategy for Ph+ ALL patients.
Collapse
|
|
47
|
Xu P, Guo D, Shao X, Peng M, Chen B. Characteristics and mutation analysis of Ph-positive leukemia patients with T315I mutation receiving tyrosine kinase inhibitors. Onco Targets Ther 2017; 10:4731-4738. [PMID: 29026321 PMCID: PMC5626416 DOI: 10.2147/ott.s142482] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
Background TKIs are the first-line treatment for patients with Ph-positive (Ph+) leukemia. However, drug resistance is frequently observed, mainly due to mutations within the breakpoint cluster region-Abelson leukemia virus (BCR-ABL) kinase domain. The T315I substitution confers complete resistance to TKIs. The aim of this study was to analyze the clinical characteristics of 17 patients with T315I mutation after TKI treatment and provide a basis for prognosis. Patients and methods The clinical data of 17 TKI-resistant Ph+ leukemia patients who were found to have a ABL kinase domain mutation from September 2008 to January 2017 were collected. Karyotypes and BCR-ABL fusion gene were analyzed by R-banding and fluorescence in situ hybridization, respectively. Total RNA was extracted by TRIzol reagent, and the ABL kinase domain mutation was detected by direct sequencing. Results A total of 17 patients reached effective remission including major molecular response and complete cytogenetic response. However, all the patients subsequently developed a T315I mutation after treatment with TKIs. The rate of the BCR-ABL fusion gene in most of the patients who developed the T315I mutation was significantly higher than that before the mutation. At initial diagnosis, patients average platelet count was 149.7×109/L, whereas the average platelet count was only 53.88×109/L after the T315I mutation (P<0.01). The results also showed that the survival time of patients with a high proportion of blast cells or a high number of white blood cells was obviously shortened. Conclusion Patients platelet count decreased when detected with the T315I mutation compared with the initial diagnosis. Combined use of different TKIs and complex chromosomal karyotypes may promote the development of the T315I mutation. When the ratio of blast cells was >50% and the number of white blood cells was >20×109/L, poor survival prognosis was observed.
Collapse
Affiliation(s)
- Peipei Xu
- Department of Hematology, Drum Tower Hospital, School of Medicine, Nanjing University
| | - Dan Guo
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, People's Republic of China
| | - Xiaoyan Shao
- Department of Hematology, Drum Tower Hospital, School of Medicine, Nanjing University
| | - Miaoxin Peng
- Department of Hematology, Drum Tower Hospital, School of Medicine, Nanjing University
| | - Bing Chen
- Department of Hematology, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, People's Republic of China
| |
Collapse
|
|
48
|
Ali MAM. Chronic Myeloid Leukemia in the Era of Tyrosine Kinase Inhibitors: An Evolving Paradigm of Molecularly Targeted Therapy. Mol Diagn Ther 2017; 20:315-33. [PMID: 27220498 DOI: 10.1007/s40291-016-0208-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm, characterized by the unrestrained expansion of pluripotent hematopoietic stem cells. CML was the first malignancy in which a unique chromosomal abnormality was identified and a pathophysiologic association was suggested. The hallmark of CML is a reciprocal chromosomal translocation between the long arms of chromosomes 9 and 22, t(9; 22)(q34; q11), creating a derivative 9q+ and a shortened 22q-. The latter, known as the Philadelphia (Ph) chromosome, harbors the breakpoint cluster region-abelson (BCR-ABL) fusion gene, encoding the constitutively active BCR-ABL tyrosine kinase that is necessary and sufficient for initiating CML. The successful implementation of tyrosine kinase inhibitors (TKIs) for the treatment of CML remains a flagship for molecularly targeted therapy in cancer. TKIs have changed the clinical course of CML; however, some patients nonetheless demonstrate primary or secondary resistance to such therapy and require an alternative therapeutic strategy. Therefore, the assessment of early response to treatment with TKIs has become an important tool in the clinical monitoring of CML patients. Although mutations in the BCR-ABL have proven to be the most prominent mechanism of resistance to TKIs, other mechanisms-either rendering the leukemic cells still dependent on BCR-ABL activity or supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling-have been identified. This article provides an overview of the current understanding of CML pathogenesis; recommendations for diagnostic tools, treatment strategies, and management guidelines; and highlights the BCR-ABL-dependent and -independent mechanisms that contribute to the development of resistance to TKIs.
Collapse
Affiliation(s)
- Mohamed A M Ali
- Department of Biochemistry, Faculty of Science, Ain Shams University, Abbassia, 11566, Cairo, Egypt.
| |
Collapse
|
|
49
|
Chelysheva E, Turkina A, Polushkina E, Shmakov R, Zeifman A, Aleshin S, Shokhin I, Guranda D, Oksenjuk O, Mordanov S, Kazakbaeva K, Chilov G. Placental transfer of tyrosine kinase inhibitors used for chronic myeloid leukemia treatment. Leuk Lymphoma 2017; 59:733-738. [DOI: 10.1080/10428194.2017.1347929] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Affiliation(s)
- Ekaterina Chelysheva
- FSBI National Research Center for Hematology of the Healthcare Ministry of the Russian Federation, Moscow, Russia
| | - Anna Turkina
- FSBI National Research Center for Hematology of the Healthcare Ministry of the Russian Federation, Moscow, Russia
| | - Evgenia Polushkina
- FSBI Scientific Center of Obstetrics, Gynecology and Perinatology of the Healthcare Ministry named after V.I. Kulakov, Moscow, Russia
| | - Roman Shmakov
- FSBI Scientific Center of Obstetrics, Gynecology and Perinatology of the Healthcare Ministry named after V.I. Kulakov, Moscow, Russia
| | - Alexey Zeifman
- FSBI N.D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| | | | - Igor Shokhin
- Center of Pharmaceutical Analytics Ltd, Moscow, Russia
| | | | - Oksana Oksenjuk
- FBEI HPE Rostov State Medical University of the Healthcare Ministry of the Russian Federation, Rostov, Russia
| | - Sergey Mordanov
- FBEI HPE Rostov State Medical University of the Healthcare Ministry of the Russian Federation, Rostov, Russia
| | - Khamida Kazakbaeva
- Research Institute of Hematology and Blood Transfusion MOH of Uzbekistan, Tashkent, Uzbekistan
| | - Ghermes Chilov
- FSBI N.D. Zelinsky Institute of Organic Chemistry of the Russian Academy of Sciences, Moscow, Russia
| |
Collapse
|
|
50
|
Latremouille-Viau D, Guerin A, Gagnon-Sanschagrin P, Dea K, Cohen BG, Joseph GJ. Health Care Resource Utilization and Costs in Patients with Chronic Myeloid Leukemia with Better Adherence to Tyrosine Kinase Inhibitors and Increased Molecular Monitoring Frequency. J Manag Care Spec Pharm 2017; 23:214-224. [PMID: 28125373 PMCID: PMC10397939 DOI: 10.18553/jmcp.2017.23.2.214] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Frequent molecular monitoring (qPCR tests), as recommended by evidence-based monitoring guidelines, is associated with higher adherence to tyrosine kinase inhibitors (TKIs) in the management of chronic myeloid leukemia (CML); both factors have been associated with better clinical and economic outcomes. OBJECTIVES To (a) estimate the effect of more frequent qPCR tests on health care resource utilization (HRU) and associated costs, including direct (effect of qPCR test frequency on HRU) and indirect (through TKI adherence) effects, and (b) develop an economic model applicable to multiple clinical practice scenarios. METHODS Adult patients newly diagnosed with CML who started TKI firstline therapy were identified from U.S. administrative claims data (2010-2015). TKI adherence (medication possession ratio [MPR]), number of inpatient days, emergency room (ER) visits, outpatient service days, and mean costs per HRU event were measured during the first year of CML treatment. Direct and indirect effects of qPCR test frequency were estimated using multivariate regression models. Subsequently, an economic model was developed to assess the overall effect of varying qPCR test frequency on HRU and associated costs during the first year of CML treatment under different clinical practice scenarios; the scenario reported is the increase from 1 to 2 qPCR tests. RESULTS Of the 1,431 patients included, 36% had no qPCR tests, the average qPCR test frequency was 1.6, and the average MPR was 0.86 during the first year of CML treatment. The direct effect of increasing qPCR test frequency by 1 was associated with 13.0% fewer inpatient days (adjusted incidence rate ratio [adjusted IRR] = 0.87; P = 0.010); 8.3% fewer ER visits (adjusted IRR = 0.92; P = 0.043); and 3.0% more outpatient service days (adjusted IRR = 1.03; P = 0.002). Each increase of 1 test was associated with an increase in TKI adherence by 2.2 percentage points (adjusted MPR difference = 0.022; P < 0.001). When considering the indirect effect of qPCR test frequency through TKI adherence, an increase of 1 qPCR test combined with an increase in TKI adherence by 2.2 percentage points was associated with a greater reduction of inpatient days from 13.0% to 15.2%, ER visits from 8.3% to 8.6%, and a smaller increase of outpatient service days from 3.0% to 2.6%. Based on the economic model, an increase from 1 to 2 qPCR tests, considering the increase in TKI adherence, was associated with a reduction of 0.87 (95% CI = -1.49, -0.18) inpatient days and 0.06 (95% CI = -0.12, 0.05) ER visits, an increase of 0.98 (95% CI = 0.25, 1.60) outpatient service days and a cost savings of $2,918 (95% CI = -5,213, -349) per patient per year. CONCLUSIONS Closer alignment with the monitoring guidelines' recommended qPCR test frequency and better adherence to TKIs were associated with lower HRU and medical service costs. Managed care initiatives to increase qPCR test frequency and TKI adherence might benefit from an enhanced reduction because of the interaction between both factors. DISCLOSURES This study was funded by Novartis Pharmaceuticals, which was involved in all stages of the study and in the decision to submit the report for publication. Latremouille-Viau, Guerin, Gagnon-Sanschagrin, and Dea are employees of Analysis Group, which received consulting fees from Novartis Pharmaceuticals for work on this study. Joseph is an employee of Novartis Pharmaceuticals and owns stock in Amgen and Pfizer. Cohen was an employee of Novartis Pharmaceuticals at the time of this study. Portions of this study were presented online (beginning May 20, 2016) as part of the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, Illinois, on June 3-7, 2016, and as a poster at the American Society of Hematology (ASH) Annual Meeting in San Diego, California, on December 3-6, 2016. Study concept and design were contributed by Latremouille-Viau and Guerin, along with the other authors. Gagnon-Sanschagrin and Dea took the lead in data collection, assisted by the other authors, and data interpretation was performed by Cohen and Joseph, along with the other authors. The manuscript was written by Latremouille-Viau, along with the other authors, and revised by Joseph, along with the other authors.
Collapse
|