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

D. H. Mak, R. Y. Wang, W. D. Schober, M. Konopleva, J. Cortes, H. Kantarjian, M. Andreeff, B. Z. Carter

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)788-794
Number of pages7
JournalLeukemia
Volume26
Issue number4
DOIs
StatePublished - Apr 1 2012
Externally publishedYes

Keywords

  • Bcl-2/Bcl-xL
  • CML
  • Mcl-1
  • XIAP
  • apoptosis
  • quiescent

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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