The stem cell factor-c-KIT pathway must be inhibited to enable apoptosis induced by BCR-ABL inhibitors in chronic

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F Belloc1, K Airiau, M Jeanneteau

  • 1Laboratoire d'Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM U876, Université Victor Ségalen, Bordeaux Cedex, France. francis.belloc@chu-bordeaux.fr

Leukemia
|January 23, 2009
PubMed

Insights

Nilotinib and imatinib induce apoptosis in chronic myelogenous leukemia (CML) cells. However, CML cells can resist nilotinib via the c-KIT pathway, suggesting combined c-KIT and BCR-ABL inhibition for effective CML treatment.

Area of Science:

  • Hematology
  • Oncology
  • Molecular Biology

Background:

  • Imatinib is a first-line therapy for chronic myelogenous leukemia (CML) targeting BCR-ABL tyrosine kinase.
  • Resistance to imatinib necessitates the development of second-generation BCR-ABL inhibitors like nilotinib.
  • Nilotinib demonstrates higher potency against BCR-ABL and efficacy against imatinib-resistant mutants.

Purpose of the Study:

  • To develop an in vitro flow cytometry assay for analyzing apoptosis induced by imatinib and nilotinib in CML cells.
  • To investigate the mechanisms of resistance to nilotinib in CML cells, particularly the role of cytokine signaling.
  • To explore potential therapeutic strategies involving combined inhibition of BCR-ABL and other signaling pathways.

Main Methods:

  • Development of a flow cytometry assay to measure apoptosis in CD34+ CML cells treated with imatinib and nilotinib.
  • Treatment of CML cells with a cytokine cocktail to assess the impact on drug-induced apoptosis.
  • Utilizing blocking antibodies against CD117 (c-KIT) and short hairpin RNA (shRNA) targeting BCR-ABL to elucidate signaling pathways.

Main Results:

  • Both imatinib and nilotinib induced significant apoptosis in CD34+ cells from CML bone marrow samples, with no effect on BCR-ABL-negative cells.
  • Cytokine-induced inhibition of apoptosis was observed with nilotinib but not imatinib, suggesting a differential resistance mechanism.
  • Inhibition of the c-KIT pathway, but not BCR-ABL signaling alone, was necessary to overcome cytokine-mediated resistance to nilotinib in K562 cells.

Conclusions:

  • The c-KIT pathway can compensate for BCR-ABL tyrosine kinase activity, promoting survival signals in CML cells.
  • Combined inhibition of c-KIT and BCR-ABL is crucial for achieving apoptosis in CML cells resistant to BCR-ABL inhibitors.
  • This study highlights a potential therapeutic strategy for overcoming resistance in CML by targeting multiple signaling pathways.

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