High caspase 3 and vulnerability to dual BCL2 family inhibition define ETO2::GLIS2 pediatric leukemia

Pediatric acute myeloid leukemia expressing the ETO2::GLIS2 fusion oncogene is associated with a poor prognosis. In a model of inducible ETO2::GLIS2 expression, the T. Mercher team demonstrates that induction of ETO2::GLIS2 leads to increased transcription and activation of CASP3 as well as cell death. In ETO2::GLIS2 leukemic cells, a strong expression of anti-apoptotic proteins of the BCL2 family (including BCL2, BCLxL, MCL1) is observed. Functional BH3-profiling analyses showed that these cells are dependent on BCL2 and MCL1. The team targeted the activity of these two proteins with two specific inhibitors and showed, in both cell lines in vitro and in patient-derived xenograft (PDX) models in vivo, that combined treatment with both molecules is required to inhibit leukemic cell growth.

This work was performed in collaboration with the CONECT-AML network led by Arnaud Petit (Hôpital Trousseau, Paris) and with the team of Patrick Auberger and Arnaud Petit (C3M, Nice).