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 ¼ 12) or germline (n ¼ 17) ND4 mutations predicted to affect translation. Somatic mutations were more likely to be heteroplasmic (Po0.001), to occur in predicted transmembrane domains (Po0.001) and were predicted to have damaging effects upon translation (Po0.001). Patients with somatically acquired ND4 mutations had significantly longer relapse-free survival (P ¼ 0.017) and overall survival (OS) (P ¼ 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 ¼ 0.052; OS: HR 0.29, CI 0.74-1.20, P ¼ 0.089). Somatic ND4 mutated patients had a higher prevalence of concomitant DNMT3A mutations (P ¼ 0.023) and a higher percentage of the NPM1/FLT3-ITD lowrisk genotype (P ¼ 0.021). Germline affected cases showed higher BAALC (P ¼ 0.036) and MLL5 (P ¼ 0.051) expression levels. Further studies are warranted to validate the favorable prognostic influence of acquired ND4 mutations in AML.

NADH dehydrogenase subunit 4 variant sequences in childhood acute myeloid leukaemia

“…In contrast to findings in adult AML (Damm et al , ), evaluation of heteroplasmic and homoplasmic MT‐ND4 subtypes separately revealed no survival advantage for heteroplasmic MT‐ND4 variant paediatric AMLs ( P = 0·73, Fig S2). This apparent contradiction between these two studies may be due to limited frequencies of MT‐ND4 variant positive AML subjects in the present study.…”

“…In accordance with previous observations in adult AML, homoplasmic F50L (UPN7), S86N (UPN8), and A131T (UPN10 + 11) variants were each defined as germline in paediatric AML samples because only variant mitochondrial DNA was detected in leukaemic and complete remission samples. Similarly, the heteroplasmic one base‐pair deletion (m.(11 032_11 038)delA) was determined to be somatic in paediatric AML case UPN4 as only leukaemia cells harboured the deletion (Fig B), confirming the results observed in adult AML (Damm et al , ).…”

“…Mutated MT‐ND4 can cause decreased Complex I activity, thus impairing mitochondrial oxidative phosphorylation (Mayr et al , ). Previously, we found MT‐ND4 variants in 6·4% of adult AML cases and somatic MT‐ND4 variants were associated with improved survival (Damm et al , ).…”

ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome

“…In this line, during the past years it has become clear that the concept of a two-hit event in leukemia with a classical 'type 1' (proliferation) and 'type 2' (differentiation) mutation 46 cannot fully explain all recent findings on molecular mutations. More and more mutations have been shown to be important for the development of leukemia including alterations in genes relevant for genomic stability like TP53, 47 metabolic enzymes (IDH1, IDH2, ND4) 5,48,49 or proteins with effects on epigenetic modification (TET2, EZH2, DNMT3A) 50,51 . 52 This leads to a high probability of multiple mutations from different pathways are randomly combined and thereby underlie the pathogenesis of AML.…”

Myeloid malignancies: mutations, models and management

“…However, additional alterations occur in genes encoding proteins that it is too early to classified into these defined categories, such as DIS3, DDX41 [23], mitochondrial NAPDH dehydrogenase ND4 [62], or cohesin complex proteins [23,63]. …”