title: Prognostic implications and molecular associations of NADH dehydrogenase subunit 4 (ND4) mutations in acute myeloid leukemia.
abstract: To study the prevalence and prognostic importance of mutations in NADH dehydrogenase subunit 4 (ND4), a mitochondrial encoded transmembrane component of the electron transport chain respiratory Complex I, 452 AML patients were examined for ND4 mutations by direct sequencing. The prognostic impact of ND4 mutations was evaluated in the context of other clinical prognostic markers and genetic risk factors. In all, 29 of 452 patients (6.4%) had either somatic (n=12) or germline (n=17) ND4 mutations predicted to affect translation. Somatic mutations were more likely to be heteroplasmic (P<0.001), to occur in predicted transmembrane domains (P<0.001) and were predicted to have damaging effects upon translation (P<0.001). Patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P=0.017) and overall survival (OS) (P=0.021) than ND4(wildtype) patients. Multivariate analysis also demonstrated a tendency for increased survival in patients with somatic ND4 mutations (RFS: hazard ratio (HR) 0.25, confidence interval (CI) 0.06-1.01, P=0.052; OS: HR 0.29, CI 0.74-1.20, P=0.089). Somatic ND4(mutated) patients had a higher prevalence of concomitant DNMT3A mutations (P=0.023) and a higher percentage of the NPM1/FLT3-ITD low-risk genotype (P=0.021). Germline affected cases showed higher BAALC (P=0.036) and MLL5 (P=0.051) expression levels. Further studies are warranted to validate the favorable prognostic influence of acquired ND4 mutations in AML.
authors.affiliation: Department of Hematology, Hemostasis, Oncology, and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Damm
authors.forename: T
authors.initials: T
authors.lastname: Bunke
authors.forename: F
authors.initials: F
authors.lastname: Thol
authors.forename: B
authors.initials: B
authors.lastname: Markus
authors.forename: K
authors.initials: K
authors.lastname: Wagner
authors.forename: G
authors.initials: G
authors.lastname: Göhring
authors.forename: B
authors.initials: B
authors.lastname: Schlegelberger
authors.forename: G
authors.initials: G
authors.lastname: Heil
authors.forename: C W M
authors.initials: CW
authors.lastname: Reuter
authors.forename: K
authors.initials: K
authors.lastname: Püllmann
authors.forename: R F
authors.initials: RF
authors.lastname: Schlenk
authors.forename: K
authors.initials: K
authors.lastname: Döhner
authors.forename: M
authors.initials: M
authors.lastname: Heuser
authors.forename: J
authors.initials: J
authors.lastname: Krauter
authors.forename: H
authors.initials: H
authors.lastname: Döhner
authors.forename: A
authors.initials: A
authors.lastname: Ganser
authors.forename: M A
authors.initials: MA
authors.lastname: Morgan
mesh_terms: D000328:Adult; D001483:Base Sequence; D014408:Biomarkers, Tumor / Q000235:genetics*; D017931:DNA Primers; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009245:NADH Dehydrogenase / Q000235:genetics*; D000090243:Nucleophosmin; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012307:Risk Factors
chemical_list: D014408:Biomarkers, Tumor; D017931:DNA Primers; C098483:NADH dehydrogenase subunit 4; C000716967:NPM1 protein, human; D000090243:Nucleophosmin; D009245:NADH Dehydrogenase