Venetoclax inhibits autophagy in chronic lymphocytic leukemia cells

Venetoclax (VCX) is a BCL2 inhibitor approved for treating B cell-derived leukemia, including chronic lymphocytic leukemia (CLL). VCX’s role in apoptosis induction is well-defined, whereas its other mechanistic roles need to be clarified. Autophagy is an intracellular degradation process involving the lysosome, playing a fundamental role in cancer cell survival and death. In this study, we aim to investigate VCX’s function in autophagy. Following the measurement of autophagic flux by western blot and fluorescent microscopy, we demonstrate that VCX is a novel autophagy inhibitor and reduces the level of the essential autophagy pathway protein ATG12 (autophagy-related 12). VCX sensitizes B cell lines and primary CLL cells to cell death induced by amino acid starvation or ibrutinib. These findings provide a rationale for VCX treatment in combination therapies that inhibit the pro-cell survival function of autophagy in B cell-derived malignancies. Abbreviations: ATG12, autophagy-related 12; BCL2, BCL2 apoptosis regulator; CLL, chronic lymphocytic leukemia; CQ, chloroquine; IBR, ibrutinib; BTK, Bruton’s tyrosine kinase; LC3B, MAP1LC3B (microtubule-associated protein 1 light chain 3 beta); VCX, venetoclax; BECN1, beclin 1