BH3 mimetic therapies for CBFA2T3::GLIS2 pediatric acute megakaryoblastic leukemia.

Pediatric acute megakaryoblastic leukemia (AMKL) associated with the CBFA2T3::GLIS2 (CG2) gene fusion is distinctive by virtue of its aggressiveness and ability to transform normal cells in a single event. The dismal therapeutic response of children to this disease has stimulated comprehensive studies on the molecular mechanism of CG2-driven tumorigenesis. In this Opinion, we highlight various investigative strategies, used in parallel by multiple independent research teams, that point to a specific dependence of CG2-expressing leukemias on the B cell leukemia/lymphoma-2 (BCL-2) family of antiapoptotic proteins. We propose that this intrinsic feature renders these leukemias particularly vulnerable to BCL-2 homology 3 (BH3) mimetics.