Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA - target gene interactions in acute myeloid leukemia

Abstract

The online version of this article has a Supplementary Appendix. BackgroundMicroRNAs are regulators of gene expression, which act mainly by decreasing mRNA levels of their multiple targets. Deregulated microRNA expression has been shown for acute myeloid leukemia, a disease also characterized by altered gene expression associated with distinct genomic aberrations such as nucleophosmin (NPM1) mutations. To shed further light on the role of deregulated microRNA and gene expression in cytogenetically normal acute myeloid leukemia with NPM1 mutation we performed an integrative analysis of microRNA and mRNA expression data sets. Design and MethodsBoth microRNA and gene expression profiles were investigated in samples from a cohort of adult cytogenetically normal acute myeloid leukemia patients (n=43; median age 46 years, range 23-60 years) with known NPM1 mutation status (n=23 mutated, n=20 wild-type) and the data were integratively analyzed. Putative microRNA-mRNA interactions were validated by quantitative reverse transcriptase polymerase chain reaction, western blotting and luciferase reporter assays. For selected microRNAs, sensitivity of microRNA-overexpressing cells to cytarabine treatment was tested by FACS viability and cell proliferation assays. ResultsOur integrative approach of analyzing both microRNA-and gene expression profiles in parallel resulted in a refined list of putative target genes affected by NPM1 mutation-associated microRNA deregulation. Of 177 putative microRNA -target mRNA interactions we identified and validated 77 novel candidates with known or potential involvement in leukemogenesis, such as IRF2-miR-20a, . Furthermore, our data showed that deregulated expression of tumor suppressor microRNAs, such as miR-29a and miR-30c, might contribute to sensitivity to cytarabine, which is observed in NPM1 mutated acute myeloid leukemia. ConclusionsOverall, our observations highlight that integrative data analysis approaches can improve insights into leukemia biology, and lead to the identification of novel microRNA -target gene interactions of potential relevance for acute myeloid leukemia treatment.Key words: microRNA, miRNA, gene expression profiling, GEP, acute myeloid leukemia, AML, NPM1 mutation.Citation: Russ AC, Sander S, Lück SC, Lang KM, Bauer M, Rücker FG, Kestler HA, Schlenk RF, Döhner H, Holzmann K, Döhner K, and Bullinger L. Integrative nucleophosmin mutation-associated microRNA and gene expression pattern analysis identifies novel microRNA -target gene interactions in acute myeloid leukemia.

Hypoxia‐induced downregulation of miR‐30c promotes epithelial‐mesenchymal transition in human renal cell carcinoma

“…(17,18) miR-30c can also trigger upregulation of transmembrane tumor necrosis factor-a expression and enhance NK cell cytotoxicity against hepatoma cell lines.…”

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

“…NPM1-mutated AML has been found to have a distinctive miRNA expression profile, [17][18][19] however, whether NPM1 is subjected to miRNA regulation is unclear. In this study, we demonstrated that a polymorphic delT in the NPM1 3'-UTR generated an illegitimate binding site for miR-337-5p.…”

Transcription factor C/EBPα-induced microRNA-30c inactivates Notch1 during granulopoiesis and is downregulated in acute myeloid leukemia

“…These observations suggest that miR-30c is a key mediator of tumor suppressor function of C/EBPa in AML; likewise, other studies in breast cancer and AML with NPM1 mutations showed a tumor suppressor-like function of miR-30c. 19,20 An in vivo investigation of the whole-mouse bone marrow cells showed an increased expression of miR-30c in granulocytes ( Figure 3A). A disruption of the C/EBPa gene in adult mice selectively blocks granulocytic development.…”

“…18 In breast cancer and AML with NPM1 mutations, miR-30c functions like a tumor suppressor. 19,20 There has been no report that shows any specific function of miR-30c in granulopoiesis and AML independent of NPM1 mutations.…”