Enhanced BCR-ABL kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in CML progenitors

Heiko Konig, M. Holtz, H. Modi, P. Manley, T. L. Holyoake, S. J. Forman, R. Bhatia

Research output: Contribution to journalArticle

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Abstract

The therapeutic success of imatinib in chronic myeloid leukemia (CML) is hampered by persistence of malignant stem cells. We investigated whether nilotinib, a more potent BCR-ABL kinase inhibitor could target CML primitive progenitors more effectively than imatinib. CML and normal progenitor cells were cultured with nilotinib or imatinib in growth factor supplemented medium. Nilotinib inhibited BCR-ABL kinase activity at lower concentrations than imatinib. Nilotinib inhibited mitogen-activated protein kinase (MAPK), AKT and STAT5 phosphorylation in CML CD34+ cells in the absence of growth factors (GFs), but did not suppress AKT and STAT5 activity, and resulted in increased MAPK activity, in the presence of GFs. Nilotinib and imatinib resulted in similar suppression of CML primitive and committed progenitors in long-term culture-initiating cell and colony-forming cell assays. Inhibition of progenitor growth was related to marked reduction in proliferation, but only a modest increase in apoptosis. Nilotinib did not show increased efficacy in reducing nondividing CML progenitors compared with imatinib. These results indicate that more potent tyrosine kinase inhibitors by themselves will not be more effective in eliminating CML progenitors than imatinib and that additional mechanism required for maintenance of malignant stem cells need to be identified to improve targeting of leukemia stem cells.

Original languageEnglish (US)
Pages (from-to)748-755
Number of pages8
JournalLeukemia
Volume22
Issue number4
DOIs
StatePublished - Apr 2008
Externally publishedYes

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Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Phosphotransferases
Growth
Stem Cells
Intercellular Signaling Peptides and Proteins
Mitogen-Activated Protein Kinases
Imatinib Mesylate
Protein-Tyrosine Kinases
4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide
Leukemia
Cell Culture Techniques
Maintenance
Phosphorylation
Apoptosis

ASJC Scopus subject areas

  • Hematology
  • Cancer Research

Cite this

Enhanced BCR-ABL kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in CML progenitors. / Konig, Heiko; Holtz, M.; Modi, H.; Manley, P.; Holyoake, T. L.; Forman, S. J.; Bhatia, R.

In: Leukemia, Vol. 22, No. 4, 04.2008, p. 748-755.

Research output: Contribution to journalArticle

Konig, Heiko ; Holtz, M. ; Modi, H. ; Manley, P. ; Holyoake, T. L. ; Forman, S. J. ; Bhatia, R. / Enhanced BCR-ABL kinase inhibition does not result in increased inhibition of downstream signaling pathways or increased growth suppression in CML progenitors. In: Leukemia. 2008 ; Vol. 22, No. 4. pp. 748-755.
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