CD84 expression stratifies venetoclax response and reveals a targetable vulnerability in resistant acute myeloid leukemia

Venetoclax-based regimens have become increasingly integrated into the therapeutic landscape of acute myeloid leukemia (AML), yet primary resistance and relapses remain major barriers to durable benefits. Building on our previous discovery of CD84 as a critical survivor and redox regulator in AML, we here demonstrate that CD84 expression contributes to venetoclax sensitivity. Low CD84 expression is associated with favorable clinical response, whereas high CD84 expression correlates with primary resistance and is up-regulated at relapse in two of three paired samples. Functional perturbation of CD84 through genetic knockdown or CD84-targeted CAR-T cells sensitized AML cells to venetoclax in vitro and in vivo cell-derived xenograft models. Mechanistically, CD84 coordinates a pro-survival program with upregulating the antioxidant stress sensor SESN2, which suppresses mitochondrial reactive oxygen species and antagonizes venetoclax-induced apoptosis. SESN2 knockdown phenocopied CD84 depletion, while SESN2 overexpression partially restored venetoclax resistance in CD84-deficient cells. Our findings suggest that CD84-mediated upregulation of SESN2 contributes to venetoclax resistance and may represent a potential therapeutic target to enhance treatment efficacy in AML.