Prognostic and Functional Relavance of microRNAs in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a highly heterogeneous disease, characterized by various cytogenetic and molecular abnormalities. MicroRNAs (miRNAs) are a class of small regulatory RNAs. The prognostic value of miRNAs in AML is yet to be determined. We performed a miRNA expression profiling study in a large cohort of AML patients (n=215) and showed strong association of specific miRNA patterns with different (cyto)genetic AML subtypes. The expression of specific sets of miRNAs are able to predict the different (cyto)genetic subtypes of AML with similar accuracy as with gene expression. In terms of risk stratification we identified miR-212 to be positively associated with favorable survival independent of established confounders in AML (HR=0.77, P=0.015 for overall survival). This finding was confirmed in an independent cohort consisting of 419 AML cases (HR=0.83, P=0.016 for overall survival). High miR-212 expression levels were associated with a gene expression profile which was significantly enriched for genes involved in the immune response. In order to identify miRNAs specifically involved in the pathogenesis of AML, we determined the expression pattern of normal granulocytic subsets. Two miRNAs, miR-9 and miR-9* (miR-9/9*) were found highly aberrantly expressed in AML but low or not expressed in normal cells from healthy individuals. Ectoptic expression of miR-9/9* in a cell line model lead to prohibition of cell differentiation, potentially by down regulation of an important hematopoietic regulation ERG. In summary, distinct miRNA expression patterns reflect the heterogeneity of AML and is able to contribute in classification, predication and might play a role in the leukemogenesis.

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