Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia
Autor: | James S. Blachly, Shelley Orwick, Jordan N. Skinner, Steven Sher, Katie Williams, Matthew Cannon, Amy Lehman, Daniel Canfield, Lindsey T. Brinton, Pu Zhang, Bonnie K. Harrington, Rosa Lapalombella, Casey Cempre, John C. Byrd, Mukul Govande, Larry Beaver, Ronni Wasmuth |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research medicine.medical_treatment Mice SCID Targeted therapy Gene Knockout Techniques chemistry.chemical_compound fluids and secretions 0302 clinical medicine hemic and lymphatic diseases Medicine CRISPR Midostaurin FLT3 Sulfonamides Aniline Compounds Hematology Myeloid leukemia Gilteritinib hemic and immune systems lcsh:Diseases of the blood and blood-forming organs lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Synergy Leukemia Myeloid Acute Proto-Oncogene Proteins c-bcl-2 Oncology Pyrazines 030220 oncology & carcinogenesis embryonic structures Female Rapid Communication BCL2 medicine.medical_specialty Combination therapy Antineoplastic Agents lcsh:RC254-282 Venetoclax 03 medical and health sciences In vivo Cell Line Tumor Internal medicine Animals Humans Protein Kinase Inhibitors Molecular Biology Acute myeloid leukemia lcsh:RC633-647.5 business.industry Genetic Therapy Bridged Bicyclo Compounds Heterocyclic Staurosporine 030104 developmental biology fms-Like Tyrosine Kinase 3 chemistry Cancer research CRISPR-Cas Systems business |
Zdroj: | Journal of Hematology & Oncology Journal of Hematology & Oncology, Vol 13, Iss 1, Pp 1-10 (2020) |
ISSN: | 1756-8722 |
Popis: | Acute myeloid leukemia (AML) is a heterogeneous and complex disease, and treatments for this disease have not been curative for the majority of patients. In younger patients, internal tandem duplication of FLT3 (FLT3-ITD) is a common mutation for which two inhibitors (midostaurin and gilteritinib) with varied potency and specificity for FLT3 are clinically approved. However, the high rate of relapse or failed initial response of AML patients suggests that the addition of a second targeted therapy may be necessary to improve efficacy. Using an unbiased large-scale CRISPR screen, we genetically identified BCL2 knockout as having synergistic effects with an approved FLT3 inhibitor. Here, we provide supportive studies that validate the therapeutic potential of the combination of FLT3 inhibitors with venetoclax in vitro and in vivo against multiple models of FLT3-ITD-driven AML. Our unbiased approach provides genetic validation for co-targeting FLT3 and BCL2 and repurposes CRISPR screening data, utilizing the genome-wide scope toward mechanistic understanding. |
Databáze: | OpenAIRE |
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