m6a and NuRD complexes regulate monocytic differentiation and resistance to BCL2/BCL2L1 inhibitors in acute myeloid leukemia

Frontline use of the BCL2 inhibitor, venetoclax, for acute myeloid leukemia (AML) has resulted in broad improvements in patient outcome. A major remaining challenge is the development of venetoclax resistance, frequently driven by compensatory transcriptional programs that promote cell survival and differentiation. These changes reduce dependence on BCL2 in favor of alternative anti-apoptotic BCL2 family members such as MCL1 or BCL2L1 (BCL-XL). Using CRISPR-based genome-wide perturbation screens, we investigated the genetic dependencies of venetoclax and the BCL2/BCL2L1 dual inhibitor AZD4320. We identified the N6-methyladenosine (m6A) writer RBM15, and the Nucleosome Remodeling and Deacetylase (NuRD) complex interactor ZMYND8 as novel mediators of resistance to both venetoclax and AZD4320. Loss of RBM15 or ZMYND8 induced drug resistance, concurrent with alterations in BCL2 family expression and monocytic differentiation. Accordingly, in AML patient samples we found reduced expression of the respective m6a or NuRD complexes was significantly associated with monocytic differentiation and ex vivo resistance to the same drugs. These findings provide critical insights into previously undescribed mechanisms of BCL2 family inhibitor resistance in AML.