BH3 mimetic therapies for childhood cancer

Mouse models of acute megakaryoblastic leukemia (AMKL) driven by CBFA2T3::GLIS2 (CG2), developed by independent teams, recapitulate human disease and constitute useful preclinical models for drug screening and validation. 

B cell leukemia/lymphoma-2 (BCL-2) transcription is regulated by CG2, and higher BCL-2 expression may increase apoptotic priming as well as sensitivity to BH3 mimetics.

Inherent BCL-xL dependence of AMKL cells causes resistance to BCL-2-specific inhibition, contrary to what is observed in acute myeloid leukemia. Hence, BCL-xL inhibitors could be useful to target AMKL, with associated thrombocytopenia as a trade-off.

To reduce the adverse effects of BCL-2- family inhibitors, therapy with BCL-2 and/or BCL-xL inhibitors, in combination with chemotherapeutic agents, JAK/ STAT inhibitors, or MAPK pathway inhibitors, may represent promising therapeutic options against CG2-driven AMKL.

https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(25)00215-1

https://sciencemission.com/BH3-mimetic-therapies-for-leukemia