Monocytic Differentiation and AHR Signaling as Primary Nodes of BET Inhibitor Response in Acute Myeloid Leukemia

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. SIGNIFICANCE: Drug resistance remains a challenge for AML, and new therapies, such as BETi, will require combination approaches to boost single-agent responses. We conducted genome-wide CRISPR screens and functional genomics on AML patient samples to identify leukemic differentiation state and AHR signaling as primary mediators of BETi response.

Automated summary

The study identified monocytic differentiation regulators and AHR signaling as primary determinants of response to BET inhibitors (BETi). Screens identified BCL2 and CDK6 as druggable vulnerabilities for rescuing BETi sensitivity. Combination of BETi with venetoclax significantly enhanced sensitivity in monocytic AML patient samples refractory to venetoclax in vitro.