The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia

Thomas O'Hare, Matthew S. Zabriskie, Christopher A. Eide, Anupriya Agarwal, Lauren T. Adrian, Huihong You, Amie S. Corbin, Fei Yang, Richard D. Press, Victor M. Rivera, Julie Toplin, Stephane Wong, Michael W. Deininger, Brian J. Druker

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

Chronic myeloid leukemia is effectively treated with imatinib, but reactivation of BCR-ABL frequently occurs through acquisition of kinase domain mutations. The additional approved ABL tyrosine kinase inhibitors (TKIs) nilotinib and dasatinib, along with investigational TKIs such as ponatinib (AP24534) and DCC-2036, support the possibility that mutation-mediated resistance in chronic myeloid leukemia can be fully controlled; however, the molecular events underlying resistance in patients lacking BCR-ABL point mutations are largely unknown. We previously reported on an insertion/truncation mutant, BCR-ABL35INS, in which structural integrity of the kinase domain is compromised and all ABL sequence beyond the kinase domain is eliminated. Although we speculated that BCR-ABL35INSis kinase-inactive, recent reports propose this mutant contributes to ABL TKI resistance.We present cell-based and biochemical evidence establishing that BCR-ABL35INS is kinase-inactive and does not contribute to TKI resistance, and we find that detection of BCR-ABL35INS does not consistently track with or explain resistance in clinical samples from chronic myeloid leukemia patients.

Original languageEnglish (US)
Pages (from-to)5250-5254
Number of pages5
JournalBlood
Volume118
Issue number19
DOIs
StatePublished - Nov 10 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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