Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia.

Autor: Niederwieser C; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Kohlschmidt J; 1] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA [2] Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA., Volinia S; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Whitman SP; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Metzeler KH; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Eisfeld AK; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Maharry K; 1] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA [2] Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA., Yan P; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Frankhouser D; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Becker H; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Schwind S; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Carroll AJ; Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA., Nicolet D; 1] The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA [2] Alliance for Clinical Trials in Oncology Statistics and Data Center, Mayo Clinic, Rochester, MN, USA., Mendler JH; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Curfman JP; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Wu YZ; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Baer MR; Department of Medicine and Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA., Powell BL; Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA., Kolitz JE; Monter Cancer Center, Hofstra North Shore-Long Island Jewish School of Medicine, Lake Success, NY, USA., Moore JO; Department of Medicine, Duke University Medical Center, Durham, NC, USA., Carter TH; Department of Internal Medicine, University of Iowa, Iowa City, IA, USA., Bundschuh R; Departments of Physics and Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA., Larson RA; Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA., Stone RM; Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA., Mrózek K; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Marcucci G; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA., Bloomfield CD; The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Jazyk: angličtina
Zdroj: Leukemia [Leukemia] 2015 Mar; Vol. 29 (3), pp. 567-75. Date of Electronic Publication: 2014 Sep 10.
DOI: 10.1038/leu.2014.267
Abstrakt: DNMT3B encodes a DNA methyltransferase implicated in aberrant epigenetic changes contributing to leukemogenesis. We tested whether DNMT3B expression, measured by NanoString nCounter assay, associates with outcome, gene and microRNA expression and DNA methylation profiles in 210 older (⩾60 years) adults with primary, cytogenetically normal acute myeloid leukemia (CN-AML). Patients were dichotomized into high versus low expressers using median cut. Outcomes were assessed in the context of known CN-AML prognosticators. Gene and microRNA expression, and DNA methylation profiles were analyzed using microarrays and MethylCap-sequencing, respectively. High DNMT3B expressers had fewer complete remissions (CR; P=0.002) and shorter disease-free (DFS; P=0.02) and overall (OS; P<0.001) survival. In multivariable analyses, high DNMT3B expression remained an independent predictor of lower CR rates (P=0.04) and shorter DFS (P=0.04) and OS (P=0.001). High DNMT3B expression associated with a gene expression profile comprising 363 genes involved in differentiation, proliferation and survival pathways, but with only four differentially expressed microRNAs (miR-133b, miR-148a, miR-122, miR-409-3p) and no differential DNA methylation regions. We conclude that high DNMT3B expression independently associates with adverse outcome in older CN-AML patients. Gene expression analyses suggest that DNMT3B is involved in the modulation of several genes, although the regulatory mechanisms remain to be investigated to devise therapeutic approaches specific for these patients.
Databáze: MEDLINE