Synergistic effect of BCL2 and FLT3 co-inhibition in acute myeloid leukemia.
J Hematol Oncol
; 13(1): 139, 2020 10 19.
Article
in En
| MEDLINE
| ID: mdl-33076970
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 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.
Key words
Full text:
1
Database:
MEDLINE
Main subject:
Leukemia, Myeloid, Acute
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Proto-Oncogene Proteins c-bcl-2
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Protein Kinase Inhibitors
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Fms-Like Tyrosine Kinase 3
Limits:
Animals
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Female
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Humans
Language:
En
Year:
2020
Type:
Article