Monocytic Subclones Confer Resistance to Venetoclax-Based Therapy in Acute Myeloid Leukemia Patients

Venetoclax-based therapy can induce responses in approximately 70% of older previously untreated acute myeloid leukemia (AML) patients. However, upfront resistance as well as relapse following initial response demonstrate the need for a deeper understanding of resistance mechanisms. In the present study, we report that responses to venetoclax + azacitidine in AML patients correlate closely with developmental stage, where phenotypically primitive AML is sensitive, but monocytic AML is more resistant. Mechanistically, resistant monocytic AML has a distinct transcriptome profile, loses expression of venetoclax target BCL2 and relies on MCL1 to mediate oxidative phosphorylation and survival. This differential sensitivity drives a selective process in patients which favors the outgrowth of monocytic subpopulations at relapse. Based on these findings, we conclude that resistance to venetoclax + azacitidine can arise due to biological properties intrinsic to monocytic differentiation. We propose that optimal AML therapies should be designed so as to independently target AML subclones that may arise at differing stages of pathogenesis.