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...
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