TY - JOUR
T1 - The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia
AU - O'Hare, Thomas
AU - Zabriskie, Matthew S.
AU - Eide, Christopher A.
AU - Agarwal, Anupriya
AU - Adrian, Lauren T.
AU - You, Huihong
AU - Corbin, Amie S.
AU - Yang, Fei
AU - Press, Richard D.
AU - Rivera, Victor M.
AU - Toplin, Julie
AU - Wong, Stephane
AU - Deininger, Michael W.
AU - Druker, Brian J.
PY - 2011/11/10
Y1 - 2011/11/10
N2 - 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.
AB - 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.
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U2 - 10.1182/blood-2011-05-349191
DO - 10.1182/blood-2011-05-349191
M3 - Article
C2 - 21908430
AN - SCOPUS:81155151860
SN - 0006-4971
VL - 118
SP - 5250
EP - 5254
JO - Blood
JF - Blood
IS - 19
ER -