title: CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations and additional chromosomal aberrations constitute molecular events in chronic myelogenous leukemia.
abstract: Progression of chronic myelogenous leukemia (CML) to accelerated (AP) and blast phase (BP) is because of secondary molecular events, as well as additional cytogenetic abnormalities. On the basis of the detection of JAK2, CBL, CBLB, TET2, ASXL1, and IDH1/2 mutations in myelodysplastic/myeloproliferative neoplasms, we hypothesized that they may also contribute to progression in CML. We screened these genes for mutations in 54 cases with CML (14 with chronic phase, 14 with AP, 20 with myeloid, and 6 with nonmyeloid BP). We identified 1 CBLB and 2 TET2 mutations in AP, and 1 CBL, 1 CBLB, 4 TET2, 2 ASXL1, and 2 IDH family mutations in myeloid BP. However, none of these mutations were found in chronic phase. No cases with JAK2V617F mutations were found. In 2 cases, TET2 mutations were found concomitant with CBLB mutations. By single nucleotide polymorphism arrays, uniparental disomy on chromosome 5q, 8q, 11p, and 17p was found in AP and BP but not involving 4q24 (TET2) or 11q23 (CBL). Microdeletions on chromosomes 17q11.2 and 21q22.12 involved tumor associated genes NF1 and RUNX1, respectively. Our results indicate that CBL family, TET2, ASXL1, and IDH family mutations and additional cryptic karyotypic abnormalities can occur in advanced phase CML.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Center, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.forename: Anna M
authors.initials: AM
authors.lastname: Jankowska
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: Christine
authors.initials: C
authors.lastname: O'Keefe
authors.forename: Simon
authors.initials: S
authors.lastname: Dujardin
authors.forename: Heather
authors.initials: H
authors.lastname: Cazzolli
authors.forename: Bartlomiej
authors.initials: B
authors.lastname: Przychodzen
authors.forename: Courtney
authors.initials: C
authors.lastname: Prince
authors.forename: John
authors.initials: J
authors.lastname: Nicoll
authors.forename: Harish
authors.initials: H
authors.lastname: Siddaiah
authors.forename: Mohammed
authors.initials: M
authors.lastname: Shaik
authors.forename: Hadrian
authors.initials: H
authors.lastname: Szpurka
authors.forename: Eric
authors.initials: E
authors.lastname: Hsi
authors.forename: Anjali
authors.initials: A
authors.lastname: Advani
authors.forename: Ronald
authors.initials: R
authors.lastname: Paquette
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D001752:Blast Crisis; D002869:Chromosome Aberrations; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D049308:Dioxygenases; D018450:Disease Progression; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D007621:Karyotyping; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics
chemical_list: C473949:ASXL1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D049308:Dioxygenases; C541081:TET2 protein, human; C492211:CBLB protein, human; D050721:Proto-Oncogene Proteins c-cbl; C067419:CBL protein, human