Schematic representation of clonal expansions in CLL and normal myeloid cells. On long-term venetoclax treatment, CLL cells undergo clonal selection resulting in expansion of the resistant clones harboring mutations in the BCL2 gene, for example, BCL2-G101V. Concomitantly, in the normal myeloid compartment, venetoclax results in clonal selection of BAX loss-of-function mutations (mBAX). Thus, venetoclax results in lineage-specific clonal expansions harboring alternative resistance mechanisms.