Monocytic differentiation and AHR signaling as Primary Nodes of BET Inhibitor Response in Acute Myeloid Leukemia.
Blood Cancer Discov
; 2(5): 518-531, 2021 09.
Article
en En
| MEDLINE
| ID: mdl-34568834
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.
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Base de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide Aguda
/
Antineoplásicos
Idioma:
En
Revista:
Blood Cancer Discov
Año:
2021
Tipo del documento:
Article