title: Prognostic and biologic significance of DNMT3B expression in older patients with cytogenetically normal primary acute myeloid leukemia.
abstract: 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.
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: C
authors.initials: C
authors.lastname: Niederwieser
authors.affiliation: 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.
authors.forename: J
authors.initials: J
authors.lastname: Kohlschmidt
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Volinia
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: S P
authors.initials: SP
authors.lastname: Whitman
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: K H
authors.initials: KH
authors.lastname: Metzeler
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: A-K
authors.initials: AK
authors.lastname: Eisfeld
authors.affiliation: 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.
authors.forename: K
authors.initials: K
authors.lastname: Maharry
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: P
authors.initials: P
authors.lastname: Yan
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: D
authors.initials: D
authors.lastname: Frankhouser
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: H
authors.initials: H
authors.lastname: Becker
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Schwind
authors.affiliation: Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Carroll
authors.affiliation: 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.
authors.forename: D
authors.initials: D
authors.lastname: Nicolet
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: J H
authors.initials: JH
authors.lastname: Mendler
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Curfman
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: Y-Z
authors.initials: YZ
authors.lastname: Wu
authors.affiliation: Department of Medicine and Greenebaum Cancer Center, University of Maryland, Baltimore, MD, USA.
authors.forename: M R
authors.initials: MR
authors.lastname: Baer
authors.affiliation: Comprehensive Cancer Center of Wake Forest University, Winston-Salem, NC, USA.
authors.forename: B L
authors.initials: BL
authors.lastname: Powell
authors.affiliation: Monter Cancer Center, Hofstra North Shore-Long Island Jewish School of Medicine, Lake Success, NY, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Kolitz
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC, USA.
authors.forename: J O
authors.initials: JO
authors.lastname: Moore
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Carter
authors.affiliation: Departments of Physics and Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bundschuh
authors.affiliation: Department of Medicine, University of Chicago Medical Center, Chicago, IL, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Larson
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Stone
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Mrózek
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Marcucci
authors.affiliation: The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
authors.forename: C D
authors.initials: CD
authors.lastname: Bloomfield
mesh_terms: D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D003561:Cytarabine / Q000627:therapeutic use; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics*; D019175:DNA Methylation; D003630:Daunorubicin / Q000627:therapeutic use; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D060828:Induction Chemotherapy; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D046228:Microarray Analysis; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D000097584:DNA Methyltransferase 3B
chemical_list: D003561:Cytarabine; D004248:DNA (Cytosine-5-)-Methyltransferases; D003630:Daunorubicin; D035683:MicroRNAs; D000097584:DNA Methyltransferase 3B