The loss of BAP1 in TP53-mutated AML drives the transformation of erythroid-primed HSPCs and is accompanied by transcriptional reprogramming and inflammatory activation. Genomic instability and epigenetic dysregulation contribute to lineage divergence toward erythroleukemia or mixed AML, respectively. BCL-xL inhibition selectively targets BAP1/TP53–deficient erythroleukemia, thereby reducing the leukemic burden and partially restoring erythropoiesis. The schematics were created with BioRender.com.