title: Frequent EVI1 translocations in myeloid blast crisis CML that evolves through tyrosine kinase inhibitors.
abstract: Clinical variables associated with ecotropic viral integration site 1 (EVI1) translocations were evaluated in 42 consecutive chronic myeloid leukemia (CML) patients in myeloid blast crisis (MBC). Translocations were confirmed with fluorescence in situ hybridization, and Western blot analysis demonstrated EVI1 expression. Translocations of EVI1 were present in 3 of 24 (12%) patients whose disease evolved MBC before tyrosine kinase inhibitor (TKI) exposure, and 7 of 18 (39%) patients who had received one or more TKIs. Univariate analysis showed that prior TKI therapy was the only clinical variable that was significantly associated with EVI1 translocation (P = 0.047). TKI-resistant BCR-ABL1 mutations were present in 71% of MBC patients with EVI1 translocations at the time of disease progression. These observations suggest that EVI1 overexpression collaborates with BCR-ABL1 in the evolution of TKI-resistant MBC. Inhibition of c-ABL kinase-mediated DNA double-strand repair by TKIs may predispose to EVI1 translocation in this setting.
authors.affiliation: UCLA Department of Medicine, Los Angeles, CA, USA. paquette@ucla.edu
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Paquette
authors.forename: John
authors.initials: J
authors.lastname: Nicoll
authors.forename: Meenal
authors.initials: M
authors.lastname: Chalukya
authors.forename: David
authors.initials: D
authors.lastname: Elashoff
authors.forename: Neil P
authors.initials: NP
authors.lastname: Shah
authors.forename: Charles
authors.initials: C
authors.lastname: Sawyers
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Spiteri
authors.forename: Gouri
authors.initials: G
authors.lastname: Nanjangud
authors.forename: P Nagesh
authors.initials: PN
authors.lastname: Rao
mesh_terms: D000328:Adult; D000368:Aged; D001752:Blast Crisis / Q000235:genetics*; D015153:Blotting, Western; D053903:DNA Breaks, Double-Stranded / Q000187:drug effects; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D019143:Evolution, Molecular; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D016313:Genes, abl; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000473:pathology*; D000074008:MDS1 and EVI1 Complex Locus Protein; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011519:Proto-Oncogenes / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014178:Translocation, Genetic
chemical_list: D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D047428:Protein Kinase Inhibitors; D014157:Transcription Factors; C406060:abl-bcr fusion protein, human; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl