Blood Journal
Leading the way in experimental and clinical research in hematology

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

  1. Karen A. Urtishak1,
  2. Alena Y. Z. Edwards1,
  3. Li-San Wang2,
  4. Amanda Hudome1,
  5. Blaine W. Robinson1,
  6. Jeffrey S. Barrett3,4,
  7. Kajia Cao2,
  8. Lori Cory1,
  9. Jonni S. Moore2,
  10. Andrew D. Bantly2,
  11. Qian-Chun Yu2,
  12. I-Ming L. Chen5,
  13. Susan R. Atlas6,
  14. Cheryl L. Willman5,
  15. Mondira Kundu7,
  16. Andrew J. Carroll8,
  17. Nyla A. Heerema9,
  18. Meenakshi Devidas10,
  19. Joanne M. Hilden11,
  20. ZoAnn E. Dreyer12,
  21. Stephen P. Hunger11,
  22. Gregory H. Reaman13, and
  23. Carolyn A. Felix1,4
  1. 1Division of Oncology, Children’s Hospital of Philadelphia, Philadelphia, PA;
  2. 2Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;
  3. 3Division of Clinical Pharmacology and Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA;
  4. 4Department of Pediatrics, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, PA;
  5. 5Department of Pathology and University of New Mexico Cancer Center and
  6. 6Department of Physics and Astronomy and University of New Mexico Cancer Center, University of New Mexico Health Services, Albuquerque, NM;
  7. 7Department of Pathology, St. Jude Children's Hospital, Memphis, TN;
  8. 8Department of Genetics, University of Alabama at Birmingham, Birmingham, AL;
  9. 9Department of Pathology, Ohio State University, Columbus, OH;
  10. 10Children’s Oncology Group, Department of Biostatistics, Gainesville, FL;
  11. 11Children’s Hospital Colorado and the University of Colorado School of Medicine, Aurora, CO;
  12. 12Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX; and
  13. 13Division of Oncology, Children’s National Medical Center, Washington, DC

Key Points

  • Infant acute lymphoblastic leukemia is sensitive to therapeutic targeting by apoptosis, necoptosis, and autophagy activation whether MLL is rearranged or germline.

  • The disease-specific form of triple death mode killing by obatoclax overcomes the intrinsic resistance of MLL-rearranged infant acute lymphoblastic to cell death.

Abstract

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.

  • Submitted April 23, 2012.
  • Accepted January 13, 2013.
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