A polymorphism in the 3'-untranslated region of the NPM1 gene causes illegitimate regulation by microRNA-337-5p and correlates with adverse outcome in acute myeloid leukemia

Abstract

ARTICLES 913Acute Myeloid Leukemia IntroductionThe NPM1 gene is frequently altered in hematologic malignancies. 1 In acute myeloid leukemia (AML), NPM1 is mainly disrupted by C-terminus mutations, causing aberrant cytoplasmic expression of the NPM1 protein.2 NPM1-mutated AML has distinctive clinicopathological and molecular features. Most notably, the mutation is closely associated with normal karyotype and relatively favorable prognosis in the absence of FLT3-internal tandem duplication (ITD).3 While genotyping the NPM1 mutations, a polymorphic nucleotide T deletion (delT) at position 1,146 of the NPM1 3'-untranslated region (UTR) was reported in 60%-70% of AML patients. 4,5 However, the significance of this polymorphism was unclear. Previous studies have shown that polymorphisms in other genes, including WT1 and IDH1, can affect AML prognosis in addition to mutations in the cognate genes.6,7 Here, we revealed that the homozygous state of the NPM1 delT polymorphism had important clinical and biological implications in AML involving an illegitimate microRNA (miRNA) regulation. Design and Methods PatientsWe analyzed 149 adult and 70 childhood patients with de novo AML; therapy-related AML or AML arising from a prior myelodysplastic syndrome were excluded. Patients' characteristics are shown in Online Supplementary Table S1. All patients gave informed consent for the study, which was approved by the Joint CUHK-NTEC Clinical Research Ethics Committee and was conducted in accordance with the Declaration of Helsinki. Patients with acute promyelocytic leukemia (APL) were excluded for survival analysis. Overall, complete survival data were available from 93 adult and 61 childhood patients with non-APL who had received treatment. All the 93 adult patients were treated with the standard cytarabine plus daunorubicin '7+3' induction chemotherapy regimen. 8 Patients who achieved complete remission (CR) were then given consolidation treatment stratified by cytogenetics. Patients with non-favorable cytogenetics were referred for assessment for allogeneic stem cell transplantation. Patients who were not eligible for transplantation and those with favorable cytogenetics were given high-dose cytarabine-based chemotherapy for consolidation. 9 Of the 61 pediatric patients, 41 were treated with a modified UK MRC AML 12 protocol 10 and 20 with the NOPHO-AML 2004 protocol, 11 as previously described. Two adult and 11 pediatric patients received transplantation as consolidation therapy. For these patients, survival data had been censored at the time of transplantation.Normal bone marrow (BM) and peripheral blood samples were obtained from healthy donors who had no prior history of malignancy. Cell cultureCell lines were cultured in RPMI-1640 medium containing 10% fetal bovine serum. Nucleophosmin, encoded by NPM1, is a haploinsufficient suppressor in hematologic malignancies. NPM1 mutations are mostly found in acute myeloid leukemia patients with normal karyotype and associated with favorable prognosis. A polymorphic nucleotide T dele...

MicroRNA polymorphisms as markers of risk, prognosis and treatment response in hematological malignancies

“…Moreover, patients with homozygous delT had significantly reduced NPM1 transcript levels as compared to the non-homozygous group. No significant correlations were found between delT homozygosity and mutations in NPM1 or other molecular markers in AML and the mechanism by which the reduction of nucleophosmin mediated by the homozygous delT polymorphism influences the outcome in AML is still unclear [61].…”

“…A compelling evidence for the role of a SNP in the 3 UTR of the NPM1 gene was presented in acute myeloid leukemia (AML) [61]. Nucleophosmin, product of the NPM1 gene, is a molecular chaperone shuffling between nucleus and cytoplasm.…”

MicroRNA binding site polymorphisms as biomarkers in cancer management and research

“…According to PolymiRTS, rs1044873 is not within any validated miRNA target. In addition, in acute myeloid leukemia, a polymorphic nucleotide T deletion is present in the 3′-UTR of NPM1 , was associated with adverse outcomes, and could independently predict shortened survival in patients with de novo acute myeloid leukemia 147. In particular, patients carrying a homozygous delT genotype had higher relapse rates (59% versus 31%; P =0.051) and significantly shortened OS (median, 9 months versus 12 months; P =0.016) and relapse-free survival (median, 5 months versus 12 months; P =0.007) than patients carrying a non homozygous genotype.…”

MicroRNAs in myeloid malignancies

“…Recently, a common NPM1 polymorphism observed in AML patients has been shown to confer worse prognosis in a mixed adult/paediatric population (Cheng et al , ). A thymine deletion in the NPM1 3′UTR allowed aberrant binding of MIR337‐5p and repression of this gene (Cheng et al , ).…”