| Literature DB >> 34568834 |
Kyle A Romine1,2, Tamilla Nechiporuk1,2, Daniel Bottomly2,3, Sophia Jeng2,4, Shannon K McWeeney2,3,4, Andy Kaempf2,5, M Ryan Corces6,7, Ravindra Majeti8, Jeffrey W Tyner9,2,10.
Abstract
To understand mechanisms of response to BET inhibitors (BETi), we mined the Beat AML functional genomic dataset and performed genome-wide CRISPR screens on BETi- sensitive and BETi- resistant AML cells. Both strategies revealed regulators of monocytic differentiation, SPI1, JUNB, FOS, and aryl-hydrocarbon receptor signaling (AHR/ARNT), as determinants of BETi response. AHR activation synergized with BETi while inhibition antagonized BETi-mediated cytotoxicity. Consistent with BETi sensitivity dependence on monocytic differentiation, ex vivo sensitivity to BETi in primary AML patient samples correlated with higher expression of monocytic markers CSF1R, LILRs, and VCAN. In addition, HL-60 cell line differentiation enhanced its sensitivity to BETi. Further, screens to rescue BETi sensitivity identified BCL2 and CDK6 as druggable vulnerabilities. Finally, monocytic AML patient samples refractory to venetoclax ex vivo were significantly more sensitive to combined BETi + venetoclax. Together, our work highlights mechanisms that could predict BETi response and identifies combination strategies to overcome resistance.Entities:
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Year: 2021 PMID： 34568834 PMCID： PMC8462123 DOI： 10.1158/2643-3230.BCD-21-0012
Source DB: PubMed Journal: Blood Cancer Discov ISSN： 2643-3230