Prognostic significance of NPM1 mutation-modulated microRNA−mRNA regulation in acute myeloid leukemia

Abstract

Distinct microRNA (miRNA) and mRNA signatures were reported in nucleophosmin (NPM1)-mutated acute myeloid leukemia (AML). However, it remains unknown whether the mutation participates in the dynamic interaction between miRNA and mRNA. In this study, we aimed to investigate the role of NPM1 mutation in modulating miRNA-mRNA regulation (MMR). From the sample-paired miRNA/mRNA microarrays of 181 de novo AML patients, we found that MMR was dynamic and could be affected by NPM1 mutation. By a systematic framework, we identified 493 NPM1 mutation-modulated MMR pairs, where the strength of MMR was significantly attenuated in patients carrying NPM1 mutations, compared to those with wild-type NPM1. These miRNAs/mRNAs were associated with pathways implicated in cancer and known functions of NPM1 mutation. Such modulation of MMR was validated in two independent cohorts as well as in cells with different NPM1 mutant burdens. Furthermore, we showed that the regulatory strength of nine MMR pairs could predict patients' outcomes. Combining these pairs, a scoring system was proposed and shown to predict survival in discovery and validation data sets, independent of other known prognostic factors. Our study provides novel biological insights into the role of NPM1 mutation as a modulator of MMR, based on which a novel prognostic marker is proposed in AML.

The human nucleophosmin 1 mutation A inhibits myeloid differentiation of leukemia cells by modulating miR-10b

“…Interestingly, MMR could be modulated by NPM1 mutation. Indeed, NPM1 mutation modulated MMR was proposed as a novel prognostic marker in AML [42]. In our current study, we observed distinct miR-10b and KLF4 mRNA signatures in NPM1-mutated AML.…”

Higher HOPX expression is associated with distinct clinical and biological features and predicts poor prognosis in de novo acute myeloid leukemia

“…21–23 Two large microarray datasets of AML with overall survival (OS) data, including The Cancer Genome Atlas (TCGA) dataset (n=186) 24 and GSE12417 [all with cytogenetically normal (CN) AML; n=162], 25 were utilized to validate the prognostic significance of HOPX . We used TCGA-normalized level-2 intensity and GSE12417 GPL96 data (profiled with Affymetrix Human Genome U133A Array), normalized as described by Metzeler et al .…”

“…Statistical analysis was carried out as described previously; 21–23 a brief description is available in the Online Supplementary Appendix .…”

Therapeutic Resistance in Acute Myeloid Leukemia: The Role of Non-Coding RNAs

“…On the other hand, expression of ncRNAs is frequently under the control of other players within these networks as well, thereby forming complex circuits which finally orchestrate malignant transformation. Among others, these networks include prominent players in leukemogenesis, such as fms-like tyrosine kinase 3 ( FLT3 ), nucleophosmin ( NPM1 ), CCAAT/Enhancer Binding Protein Alpha ( CEBPA ), tumor protein P53 ( TP53 ) or the RAS-mitogen-activated protein kinase/extracellular signal-regulated kinase (RAS-MAPK/ERK) signaling cascade [19,20,21,22,23]. Lately, the role of ncRNA in mediating sensitivity and resistance to cytotoxic agents, respectively, has been discovered, which makes them attractive targets of novel anti-cancer therapies.…”