MicroRNA Signatures Associated with Cytogenetics and Outcome in Acute Myeloid Leukemia.

MicroRNAs are small non-coding RNAs of 19–25 nucleotides in length that are negative regulators of gene expression. Findings over the last few years indicate that microRNAs are involved in fundamental cellular process, including development and hematopoietic differentiation. Acute myeloid leukemia (AML) is a heterogeneous disorder that is characterized by proliferation of immature cells. Although there are well defined molecular subtypes of AML, the pathogenesis in the majority of cases is largely unknown. Focusing on known genes will not likely suffice to uncover the nature of the AML. The integration of a whole genome approach including non-coding RNA gene products may lead to an improve understanding of the biology of AML.

Methods: To determine whether microRNAs are associated with known cytogenetic abnormalities and biological features in AML, we evaluated the microRNA expression profiles of 176 samples of adult AML with intermediate and poor risk cytogenetics and 10 CD34+ cells from healthy donors using a microarrays platform. After normalization, data were analyzed using significance analysis of microarrays and prediction analysis of microarrays software. An independent set of 28 patients with AML was used to validate the signatures using quantitative real time PCR. Treatment response was evaluated in 29 newly AML diagnosed patients 4 to 6 weeks after induction chemotherapy with idarubicin and cytarabine by bone marrow examination. Complete remission was defined as less than 5% blasts in the bone marrow. Otherwise it was categorized as resistant disease.

Results: We found several microRNAs differentially expressed between CD34+ cells and all the AML samples. A subset of these microRNAs reflects the differentiation stage of the leukemias and correlate with the French-American-British classification of AML. Likewise, microRNAs are closely associated with the prevalent cytogenetic abnormalities. A common signature including the over expressed miR-20; miR-17, miR-25 and miR-191 are associated with short overall survival, while miR-29b is found down-regulated in patients with resistant disease. Furthermore, we proved experimentally that miR-29b regulates negatively MCL-1, a critical apoptosis regulator, which has been found up-regulated and associated with relapse and chemotherapy resistance in leukemia.

Conclusions: MicroRNAs expression in AML is closely associated with differentiation stage, morphology and cytogenetics. A subset of MicroRNAs is correlated with survival and treatment response.