title: Resistance to imatinib in patients with chronic myelogenous leukemia and the splice variant BCR-ABL1(35INS).
abstract: In patients with chronic myelogenous leukemia (CML), point mutations in the BCR-ABL1 kinase domain are the most common cause of treatment failure with a tyrosine kinase inhibitor (TKI). It is not clear whether the splice variant BCR-ABL1(35INS) is also associated with treatment failure.
  
  
  
  We reviewed all CML patients who had BCR-ABL1 kinase mutation analysis performed between August 1, 2007, and January 15, 2014. Patients who had BCR-ABL1(35INS) detected had their medical records reviewed to determine response to TKI therapy.
  
  
  
  Two hundred and eighty four patients had kinase mutation testing performed; of these, 64 patients (23%) had BCR-ABL1(35INS) detected. Forty-five patients were in chronic phase (70%), 10 were in accelerated phase (16%), 6 were in blastic phase (9%), and 3 were in other settings (5%). Of the 34 chronic phase patients who began therapy with imatinib, 23 patients (68%) failed therapy: 8 patients (24%) had primary refractory disease, 11 patients (32%) progressed, and 4 patients (12%) had disease progression after dose interruption. In contrast to the patients with disease progression or lack of response, none of 23 patients who were responding to imatinib had BCR-ABL1(35INS) detected. DNA sequencing of commonly mutated spliceosomal genes SF3B1, U2AF1, SRSF2, ZRSR2, SFA31, PRPF408, U2A565, and SF1 did not reveal mutations in seven BCR-ABL1(35INS) -positive patients tested.
  
  
  
  The splice variant BCR-ABL1(35INS) is frequently found in patients who are resistant to imatinib. Mutations in the commonly mutated spliceosomal proteins do not contribute to this association.
authors.affiliation: Leukemia Service, Department of Medicine, USA. Electronic address: bermane@mskcc.org.
authors.forename: Ellin
authors.initials: E
authors.lastname: Berman
authors.affiliation: Cytogenetics Laboratory, USA.
authors.forename: Suresh
authors.initials: S
authors.lastname: Jhanwar
authors.affiliation: Department of Pathology, New York University Langone Medical Center, USA.
authors.forename: Cyrus
authors.initials: C
authors.lastname: Hedvat
authors.affiliation: Department of Pathology, New York University Langone Medical Center, USA.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Arcila
authors.affiliation: Leukemia Service, Department of Medicine, USA; Human Oncology and Pathogenesis Program, USA.
authors.forename: Omar Abdel-
authors.initials: OA
authors.lastname: Wahab
authors.affiliation: Leukemia Service, Department of Medicine, USA; Human Oncology and Pathogenesis Program, USA.
authors.forename: Ross
authors.initials: R
authors.lastname: Levine
authors.affiliation: Adult Bone Marrow Transplant Service, all Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY, USA.
authors.forename: Molly
authors.initials: M
authors.lastname: Maloy
authors.affiliation: NeoGenomic Laboratories, Irvine, CA, USA.
authors.forename: Wanlong
authors.initials: W
authors.lastname: Ma
authors.affiliation: NeoGenomic Laboratories, Irvine, CA, USA.
authors.forename: Maher
authors.initials: M
authors.lastname: Albitar
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D012326:RNA Splicing / Q000235:genetics*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D055815:Young Adult
chemical_list: D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate
keywords: CML; Resistance to imatinib; Splice variant