Unknown,Transcriptomics,Genomics,Proteomics

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

ABSTRACT: Background: MicroRNAs are regulators of gene expression, mainly functioning 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 further illuminate 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 Methods: Both microRNA and gene expression profiles were measured in a cohort of 43 adult acute myeloid leukemia patient samples (n=42 cytogenetically normal, n=1 del7q; median age 46 years [range 23-60]) of known NPM1 mutation status (n=23 mutated, n=20 wild-type) and data integratively analyzed. Putative microRNA-mRNA interactions were validated by quantitative RT-PCR, Western Blot and luciferase reporter assays. For selected microRNAs, sensitivity of microRNA-overexpressing cells to cytarabine treatment was tested by FACS viability and cell proliferation assays. Results: Our 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 could identify and validate 77 novel candidates with known or potential implication in leukemogenesis, such as IRF2-miR-20a, KIT-miR-20a and MN1-miR-15a. Furthermore, our data showed that deregulated expression of tumor suppressor microRNAs such as miR-29a and miR-30c might contribute to the sensitivity to cytarabine, which is observed in NPM1-mutated acute myeloid leukemia. Conclusions: Overall, 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. MicroRNA and gene expression profiles were measured in a cohort of 43 adult (42 cytogenetically normal and 1 del7q) acute myeloid leukemia patient samples of known NPM1 mutation status (n=23 mutated, n=20 wild-type). This submission represents the mRNA expression component of the study. The miRNA expression data will be deposited as supplementary information along with the accompanying manuscript.

ORGANISM(S): Homo sapiens

SUBMITTER: Lars Bullinger

PROVIDER: E-GEOD-31644 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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

Russ Annika C AC Sander Sandrine S Lück Sonja C SC Lang Katharina M KM Bauer Marion M Rücker Frank G FG Kestler Hans A HA Schlenk Richard F RF Döhner Hartmut H Holzmann Karlheinz K Döhner Konstanze K Bullinger Lars L

Haematologica 20110831 12

<h4>Background</h4>MicroRNAs 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 p ...[more]

PMID: 21880628

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

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

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