title: High DNA methyltransferase DNMT3B levels: a poor prognostic marker in acute myeloid leukemia.
abstract: It has been recently shown that DNA methyl transferase overexpression is correlated with unfavourable prognosis in human malignancies while methylation deregulation remains a hallmark that defines acute myeloid leukemia (AML). The oncogenic transcription factor EVI1 is involved in methylation deregulation and its overexpression plays a major role for predicting an adverse outcome. Moreover, the identification of DNMT3A mutations in AML patients has recently been described as a poor prognostic indicator. In order to clarify relationship between these key actors in methylation mechanisms and their potential impact on patient outcomes, we analysed 195 de novo AML patients for the expression of DNMT3A, 3B (and its non-catalytic variant 3B(NC)) and their correlations with the outcome and the expression of other common prognostic genetic biomarkers (EVI1, NPM1, FLT3ITD/TKD and MLL) in adult AML. The overexpression of DNMT3B/3B(NC) is (i) significantly correlated with a shorter overall survival, and (ii) inversely significantly correlated with event-free survival and DNMT3A expression level. Moreover, multivariate analysis showed that a high expression level of DNMT3B/3B(NC) is statistically a significant independent poor prognostic indicator. This study represents the first report showing that the overexpression of DNMT3B/3B(NC) is an independent predictor of poor survival in AML. Its quantification should be implemented to the genetic profile used to stratify patients for therapeutical strategies and should be useful to identify patients who may benefit from therapy based on demethylating agents.
authors.affiliation: Service d'Hématologie Biologique, Centre Hospitalier Lyon-Sud, Pierre-Bénite France, Hospices Civils de Lyon, Lyon, France. sandrine.hayette@chu-lyon.fr
authors.forename: Sandrine
authors.initials: S
authors.lastname: Hayette
authors.forename: Xavier
authors.initials: X
authors.lastname: Thomas
authors.forename: Laurent
authors.initials: L
authors.lastname: Jallades
authors.forename: Kaddour
authors.initials: K
authors.lastname: Chabane
authors.forename: Carole
authors.initials: C
authors.lastname: Charlot
authors.forename: Isabelle
authors.initials: I
authors.lastname: Tigaud
authors.forename: Sophie
authors.initials: S
authors.lastname: Gazzo
authors.forename: Stéphane
authors.initials: S
authors.lastname: Morisset
authors.forename: Pascale
authors.initials: P
authors.lastname: Cornillet-Lefebvre
authors.forename: Adriana
authors.initials: A
authors.lastname: Plesa
authors.forename: Sarah
authors.initials: S
authors.lastname: Huet
authors.forename: Aline
authors.initials: A
authors.lastname: Renneville
authors.forename: Gilles
authors.initials: G
authors.lastname: Salles
authors.forename: Franck Emmanuel
authors.initials: FE
authors.lastname: Nicolini
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Magaud
authors.forename: Mauricette
authors.initials: M
authors.lastname: Michallet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D014408:Biomarkers, Tumor / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry / Q000378:metabolism*; D000090205:DNA Methyltransferase 3A; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D005091:Exons / Q000235:genetics; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D015999:Multivariate Analysis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000090243:Nucleophosmin; D011379:Prognosis; D016415:Sequence Alignment; D016896:Treatment Outcome; D055815:Young Adult; D000097584:DNA Methyltransferase 3B
chemical_list: D014408:Biomarkers, Tumor; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D009363:Neoplasm Proteins; D000090243:Nucleophosmin; D000097584:DNA Methyltransferase 3B; C000717967:DNMT3A protein, human; C000716967:NPM1 protein, human