Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia
Open Access
- 19 October 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Journal of Hematology & Oncology
- Vol. 13 (1), 1-10
- https://doi.org/10.1186/s13045-020-00973-4
Abstract
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 ofFLT3(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 ofFLT3-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.Keywords
Funding Information
- Foundation for the National Institutes of Health (5P30CA016058, 5R01CA223165, R35 CA197734)
- storagereview.com (Grant of Equipment from StorageReview.com)
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