Activation of apoptosis signaling eliminates CD34+ progenitor cells in blast crisis CML independent of response to tyrosine kinase inhibitors

Leukemia. 2012 Apr;26(4):788-94. doi: 10.1038/leu.2011.285. Epub 2011 Oct 28.


Despite being highly effective for newly diagnosed chronic myeloid leukemia (CML), imatinib not only is inactive against quiescent CML stem cells, but also has limited activity against blast crisis (BC) CML. The relative activity of Bcr-Abl and the expression levels of antiapoptotic proteins in proliferating and quiescent CD34(+) BC CML progenitor cells and the effects of targeting antiapoptotic proteins in these cells are unknown. Here we report higher levels of p-CrkL in quiescent than in proliferating CD34(+) progenitor cells and comparable expression levels of Bcl-2, Bcl-xL, Mcl-1 and XIAP in the two populations in BC CML. Inhibition of Bcl-2/Bcl-xL by ABT-737 in cells from patients with tyrosine kinase inhibitor (TKI)-resistant BC CML promoted apoptosis in quiescent CD34(+) progenitor cells with an efficacy similar to that in proliferating cells. Combination of ABT-737 with imatinib (which decreases Mcl-1 levels) or triptolide (which decreases Mcl-1 and XIAP) synergistically induced death of both proliferating and quiescent CD34(+) progenitor cells obtained from TKI-resistant BC CML patients. These results suggest that antiapoptotic proteins are critical targets in BC CML and that activation of apoptosis signaling can eliminate both proliferating and quiescent CD34(+) progenitor cells in BC CML, independent of response to TKIs.

Publication types

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

MeSH terms

  • Antigens, CD34 / analysis*
  • Apoptosis / drug effects*
  • Benzamides
  • Biphenyl Compounds / pharmacology
  • Blast Crisis / pathology*
  • Cell Line, Tumor
  • Diterpenes / pharmacology
  • Epoxy Compounds / pharmacology
  • Fusion Proteins, bcr-abl / physiology
  • Hematopoietic Stem Cells / drug effects*
  • Humans
  • Imatinib Mesylate
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / drug therapy
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Nitrophenols / pharmacology
  • Phenanthrenes / pharmacology
  • Piperazines / pharmacology
  • Protein Kinase Inhibitors / pharmacology*
  • Protein-Tyrosine Kinases / antagonists & inhibitors*
  • Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors
  • Pyrimidines / pharmacology
  • RNA, Messenger / analysis
  • Signal Transduction / physiology*
  • Sulfonamides / pharmacology


  • ABT-737
  • Antigens, CD34
  • Benzamides
  • Biphenyl Compounds
  • Diterpenes
  • Epoxy Compounds
  • Nitrophenols
  • Phenanthrenes
  • Piperazines
  • Protein Kinase Inhibitors
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrimidines
  • RNA, Messenger
  • Sulfonamides
  • triptolide
  • Imatinib Mesylate
  • Protein-Tyrosine Kinases
  • Fusion Proteins, bcr-abl