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BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism

J Liu1, S Joha, T Idziorek

  • 1INSERM, Unité 837, Equipe 3, Institut de Recherche sur le Cancer de Lille, Lille, France.

Leukemia
|January 25, 2008
PubMed

Insights

Sequential Abl kinase inhibitor therapy can create resistant chronic myeloid leukemia cells. These mutated cells protect non-mutated cells via paracrine signaling, suggesting JAK2 inhibition as a potential treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Imatinib-resistant chronic myeloid leukemia (CML) can be treated with dasatinib.
  • Sequential kinase inhibitor therapy can drive BCR-ABL mutations, leading to broad drug resistance.

Purpose of the Study:

  • To model the evolution of drug resistance in CML.
  • To investigate the mechanisms by which resistant CML cells interact with and protect sensitive cells.

Main Methods:

  • Exposure of a BCR-ABL(+) mouse leukemic cell line (DA1-3b) sequentially to imatinib and then dasatinib.
  • Characterization of emergent mutations (E255K, T315I, V299L).
  • Co-culture experiments to assess the protective effects of mutated cells on non-mutated cells, including pathway analysis (MEK/ERK, JAK2/STAT5) and blockade studies.

Main Results:

  • Sequential treatment generated CML cells with E255K and T315I mutations.
  • Mutated CML cells protected non-mutated cells in co-culture through paracrine signaling, involving IL-3, MEK/ERK, and JAK2/STAT5 pathways.
  • As little as 10% mutated cells conferred protection; JAK2 and MEK1/2 inhibition blocked this effect.
  • Mutated cells were sensitive to JAK2 inhibition.

Conclusions:

  • Sequential Abl kinase inhibitor therapy can lead to the emergence of resistant CML cell sub-populations.
  • These resistant cells can protect sensitive cells via paracrine mechanisms, potentially hindering treatment efficacy.
  • Targeting JAK2 may be a viable strategy to eliminate both mutated and non-mutated CML cells.

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