CBFA2T3::GLIS2 Pediatric Acute Megakaryoblastic Leukemia is Sensitive to BCL-XL Inhibition by Navitoclax and DT2216.

Acute megakaryoblastic leukemia (AMKL) is a rare, developmentally restricted and highly lethal cancer of early childhood. The paucity and hypocellularity (due to myelofibrosis) of primary patient samples hamper the discovery of cell- and genotype-specific treatments. AMKL is driven by mutually exclusive chimeric fusion oncogenes in two thirds of cases, with CBFA2T3::GLIS2 (CG2) and NUP98 fusions (NUP98r) representing the highest fatality subgroups. We established CD34+ cord blood-derived CG2 models (n=6) that sustain serial transplantation and recapitulate human leukemia regarding immunophenotype, leukemia initiating cell frequencies, co-mutational landscape and gene expression signature with distinct upregulation of the pro-survival factor BCL2. Cell membrane proteomic analyses highlighted CG2 surface markers preferentially expressed on leukemic cells compared to CD34+ cells (e.g. NCAM1, CD151). AMKL differentiation block in the mega-erythroid progenitor space was confirmed by single cell profiling. While CG2 cells were rather resistant to BCL2 genetic knockdown or selective pharmacological inhibition with Venetoclax, they were vulnerable to strategies that target the megakaryocytic pro-survival factor BCL-XL (BCL2L1), including in vitro and in vivo treatment with BCL2/BCL-XL/BCL-W inhibitor Navitoclax and DT2216, a selective BCL-XL PROTAC (proteolysis-targeting chimera) degrader developed to limit thrombocytopenia in patients. NUP98r AMKL were also sensitive to BCL-XL inhibition, but not the NUP98r monocytic leukemia, pointing to a lineage-specific dependency. Navitoclax or DT2216 treatment in combination with low dose cytarabine further reduced leukemic burden in mice. This work extends the cellular and molecular diversity set of human AMKL models and uncovers BCL-XL as a therapeutic vulnerability in CG2 and NUP98r AMKL.

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