title: The BCR-ABL35INS insertion/truncation mutant is kinase-inactive and does not contribute to tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
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-ABL(35INS), 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-ABL(35INS) is kinase-inactive, recent reports propose this mutant contributes to ABL TKI resistance. We present cell-based and biochemical evidence establishing that BCR-ABL(35INS) is kinase-inactive and does not contribute to TKI resistance, and we find that detection of BCR-ABL(35INS) does not consistently track with or explain resistance in clinical samples from chronic myeloid leukemia patients.
authors: Division of Hematology and Medical Oncology, Oregon Health & Science University Knight Cancer Institute, Portland, USA. Thomas.OHare@hci.utah.edu
authors: Thomas
authors: T
authors: O'Hare
authors: Matthew S
authors: MS
authors: Zabriskie
authors: Christopher A
authors: CA
authors: Eide
authors: Anupriya
authors: A
authors: Agarwal
authors: Lauren T
authors: LT
authors: Adrian
authors: Huihong
authors: H
authors: You
authors: Amie S
authors: AS
authors: Corbin
authors: Fei
authors: F
authors: Yang
authors: Richard D
authors: RD
authors: Press
authors: Victor M
authors: VM
authors: Rivera
authors: Julie
authors: J
authors: Toplin
authors: Stephane
authors: S
authors: Wong
authors: Michael W
authors: MW
authors: Deininger
authors: Brian J
authors: BJ
authors: Druker
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D001549:Benzamides; D045744:Cell Line, Tumor; D004273:DNA, Neoplasm / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016313:Genes, abl; D006801:Humans; D054643:INDEL Mutation; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000494:pharmacology; D055815:Young Adult
chemical_list: D001549:Benzamides; D004273:DNA, Neoplasm; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl