Relative Mitochondrial Priming of Myeloblasts and Normal HSCs Determines Chemotherapeutic Success in AML

Cell. 2012 Oct 12;151(2):344-55. doi: 10.1016/j.cell.2012.08.038.

Abstract

Despite decades of successful use of cytotoxic chemotherapy in acute myelogenous leukemia (AML), the biological basis for its differential success among individuals and for the existence of a therapeutic index has remained obscure. Rather than taking a genetic approach favored by many, we took a functional approach to ask how differential mitochondrial readiness for apoptosis ("priming") might explain individual variation in clinical behavior. We found that mitochondrial priming measured by BH3 profiling was a determinant of initial response to induction chemotherapy, relapse after remission, and requirement for allogeneic bone marrow transplantation. Differential priming between malignant myeloblasts and normal hematopoietic stem cells supports a mitochondrial basis to the therapeutic index for chemotherapy. BH3 profiling identified BCL-2 inhibition as a targeted strategy likely to have a useful therapeutic index. BH3 profiling refines predictive information provided by conventional biomarkers currently in use and thus may itself have utility as a clinical predictive biomarker. PAPERCLIP:

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Granulocyte Precursor Cells / metabolism
  • Hematopoietic Stem Cell Transplantation
  • Hematopoietic Stem Cells / pathology
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / pathology*
  • Leukemia, Myeloid, Acute / therapy
  • Mitochondria / physiology*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Topoisomerase II Inhibitors / therapeutic use
  • Tumor Cells, Cultured

Substances

  • Proto-Oncogene Proteins c-bcl-2
  • Topoisomerase II Inhibitors