Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia

Karen A. Urtishak, Alena Y.Z. Edwards, Li San Wang, Amanda Hudome, Blaine W. Robinson, Jeffrey S. Barrett, Kajia Cao, Lori Cory, Jonni S. Moore, Andrew D. Bantly, Qian Chun Yu, I. Ming L. Chen, Susan R. Atlas, Cheryl L. Willman, Mondira Kundu, Andrew J. Carroll, Nyla A. Heerema, Meenakshi Devidas, Joanne M. Hilden, Zo Ann E. DreyerStephen P. Hunger, Gregory H. Reaman, Carolyn A. Felix

Research output: Contribution to journalArticlepeer-review


Survival in infants younger than 1 year who have acute lymphoblastic leukemia (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-antiapoptotic 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, half maximal effective concentrations (EC50s) were lower than 176 nM (the maximal plasma concentration [Cmax] with recommended adult dose) in 76% of samples, whether in MLL-AF4, MLL-ENL, or 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 a rationale to incorporate a similarly acting compound into combination strategies to combat infant ALL.

Original languageEnglish (US)
Pages (from-to)2689-2703
Number of pages15
Issue number14
StatePublished - 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology


Dive into the research topics of 'Potent obatoclax cytotoxicity and activation of triple death mode killing across infant acute lymphoblastic leukemia'. Together they form a unique fingerprint.

Cite this