TY - JOUR
T1 - Monocytic Differentiation and AHR Signaling as Primary Nodes of BET Inhibitor Response in Acute Myeloid Leukemia
AU - Romine, Kyle A.
AU - Nechiporuk, Tamilla
AU - Bottomly, Daniel
AU - Jeng, Sophia
AU - McWeeney, Shannon K.
AU - Kaempf, Andy
AU - Corces, M. Ryan
AU - Majeti, Ravindra
AU - Tyner, Jeffrey W.
N1 - Publisher Copyright:
©2021 American Association for Cancer Research.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - To understand mechanisms of response to BET inhibitors (BETi), we mined the Beat AML functional genomic data set and performed genome-wide CRISPR screens on BETi-sensitive and BETi-resistant acute myeloid leukemia (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, whereas 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 the 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.
AB - To understand mechanisms of response to BET inhibitors (BETi), we mined the Beat AML functional genomic data set and performed genome-wide CRISPR screens on BETi-sensitive and BETi-resistant acute myeloid leukemia (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, whereas 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 the 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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U2 - 10.1158/2643-3230.BCD-21-0012
DO - 10.1158/2643-3230.BCD-21-0012
M3 - Article
C2 - 34568834
AN - SCOPUS:85124615100
SN - 2643-3230
VL - 2
SP - 518
EP - 531
JO - Blood cancer discovery
JF - Blood cancer discovery
IS - 5
ER -