title: Mutational spectrum analysis of chronic myelomonocytic leukemia includes genes associated with epigenetic regulation: UTX, EZH2, and DNMT3A.
abstract: Chronic myelomonocytic leukemia (CMML), a myelodysplastic/myeloproliferative neoplasm, is characterized by monocytic proliferation, dysplasia, and progression to acute myeloid leukemia. CMML has been associated with somatic mutations in diverse recently identified genes. We analyzed 72 well-characterized patients with CMML (N = 52) and CMML-derived acute myeloid leukemia (N = 20) for recurrent chromosomal abnormalities with the use of routine cytogenetics and single nucleotide polymorphism arrays along with comprehensive mutational screening. Cytogenetic aberrations were present in 46% of cases, whereas single nucleotide polymorphism array increased the diagnostic yield to 60%. At least 1 mutation was found in 86% of all cases; novel UTX, DNMT3A, and EZH2 mutations were found in 8%, 10%, and 5.5% of patients, respectively. TET2 mutations were present in 49%, ASXL1 in 43%, CBL in 14%, IDH1/2 in 4%, KRAS in 7%, NRAS in 4%, and JAK2 V617F in 1% of patients. Various mutant genotype combinations were observed, indicating molecular heterogeneity in CMML. Our results suggest that molecular defects affecting distinct pathways can lead to similar clinical phenotypes.
authors.affiliation: Department of Translational Hematology and Oncology Research, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Jankowska
authors.forename: Hideki
authors.initials: H
authors.lastname: Makishima
authors.forename: Ramon V
authors.initials: RV
authors.lastname: Tiu
authors.forename: Hadrian
authors.initials: H
authors.lastname: Szpurka
authors.forename: Yun
authors.initials: Y
authors.lastname: Huang
authors.forename: Fabiola
authors.initials: F
authors.lastname: Traina
authors.forename: Valeria
authors.initials: V
authors.lastname: Visconte
authors.forename: Yuka
authors.initials: Y
authors.lastname: Sugimoto
authors.forename: Courtney
authors.initials: C
authors.lastname: Prince
authors.forename: Christine
authors.initials: C
authors.lastname: O'Keefe
authors.forename: Eric D
authors.initials: ED
authors.lastname: Hsi
authors.forename: Alan
authors.initials: A
authors.lastname: List
authors.forename: Mikkael A
authors.initials: MA
authors.lastname: Sekeres
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
authors.forename: Michael A
authors.initials: MA
authors.lastname: McDevitt
authors.forename: Jaroslaw P
authors.initials: JP
authors.lastname: Maciejewski
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002869:Chromosome Aberrations; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D015477:Leukemia, Myelomonocytic, Chronic / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D063151:Polycomb Repressive Complex 2; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D009687:Nuclear Proteins; D014157:Transcription Factors; D056466:Histone Demethylases; C523998:KDM6A protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2