Bcl-xL anti-apoptotic network is dispensable for development and maintenance of CML but is required for disease progression where it represents a new therapeutic target

Leukemia. 2013 Oct;27(10):1996-2005. doi: 10.1038/leu.2013.151. Epub 2013 May 14.

Abstract

The dismal outcome of blast crisis chronic myelogenous leukemia (CML-BC) patients underscores the need for a better understanding of the mechanisms responsible for the development of drug resistance. Altered expression of the anti-apoptoticBcl-xL has been correlated with BCR-ABL leukemogenesis; however, its involvement in the pathogenesis and evolution of CML has not been formally demonstrated yet. Thus, we generated an inducible mouse model in which simultaneous expression of p210-BCR-ABL1 and deletion of bcl-x occurs within hematopoietic stem and progenitor cells. Absence of Bcl-xL did not affect development of the chronic phase-like myeloproliferative disease, but none of the deficient mice progressed to an advanced phenotype, suggesting the importance of Bcl-xL in survival of progressing early progenitor cells. Indeed, pharmacological antagonism of Bcl-xL, with ABT-263, combined with PP242-induced activation of BAD markedly augmented apoptosis of CML-BC cell lines and primary CD34(+) progenitors but not those from healthy donors, regardless of drug resistance induced by bone marrow stromal cell-generated signals. Moreover, studies in which BAD or Bcl-xL expression was molecularly altered strongly support their involvement in ABT-263/PP242-induced apoptosis of CML-BC progenitors. Thus, suppression of the antiapoptotic potential of Bcl-xL together with BAD activation represents an effective pharmacological approach for patients undergoing blastic transformation.

Publication types

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

MeSH terms

  • Aniline Compounds / pharmacology
  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Blast Crisis / drug therapy
  • Blast Crisis / genetics
  • Blast Crisis / pathology*
  • Disease Progression
  • Female
  • Flow Cytometry
  • Fusion Proteins, bcr-abl / antagonists & inhibitors
  • Fusion Proteins, bcr-abl / genetics
  • Humans
  • Indoles / pharmacology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Male
  • Mice
  • Mice, Transgenic
  • Purines / pharmacology
  • Stem Cells / drug effects
  • Stem Cells / metabolism
  • Stem Cells / pathology*
  • Sulfonamides / pharmacology
  • bcl-X Protein / antagonists & inhibitors*
  • bcl-X Protein / metabolism

Substances

  • Aniline Compounds
  • Antineoplastic Agents
  • Indoles
  • Purines
  • Sulfonamides
  • bcl-X Protein
  • Fusion Proteins, bcr-abl
  • PP242
  • navitoclax