Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia (ALL)
Menée in vitro sur des cellules prélevées chez 54 enfants atteints d'une leucémie lymphoblastique aiguë avant l'âge d'un an, cette étude met en évidence des mécanismes d'action de l'obatoclax
Survival in infants <1 year old with ALL is inferior whether MLL is rearranged (R) or germline (G). MLL translocations confer chemotherapy resistance and infants experience excess complications. We characterized in vitro sensitivity to the pan-anti-apoptotic BCL-2 family inhibitor obatoclax mesylate in diagnostic leukemia cells from 54 infants with ALL/bilineal acute leukemia because of the role of prosurvival BCL-2 proteins in resistance, their imbalanced expression in infant ALL, and evidence of obatoclax activity with a favorable toxicity profile in early adult leukemia trials. Overall, EC50s were <176 nM (Cmax with recommended adult dose) in 76% of samples whether in MLL-AF4, MLL-ENL, other MLL-R or MLL-G subsets, and regardless of patients' poor prognostic features. However, MLL status and partner genes correlated with EC50. Combined approaches including flow cytometry, Western blot, obatoclax treatment with death pathway inhibition, microarray analyses and/or electron microscopy indicated a unique killing mechanism involving apoptosis, necroptosis and autophagy in MLL-AF4 ALL cell lines and primary MLL-R and MLL-G infant ALL cells. This in vitro obatoclax activity and its multiple killing mechanisms across molecular cytogenetic subsets provide rationale to incorporate a similarly acting compound into combination strategies to combat infant ALL.