Microrna-211 - a Novel Oncogene in Acute Myeloid Leukemia

MicroRNAs are a class of small, non-coding RNA molecules that regulate gene expression by post-transcriptional silencing and regulate many critical cellular processes. In cancer, microRNAs are emerging as important biomarkers of disease and a subset of microRNAs have well-established roles as drivers of cancer development. MicroRNA-211 (miR-211) is an intronic microRNA encoded on human chromosome 15, and deregulated miR-211 expression has been previously demonstrated in melanoma and a range of other cancers. A role for miR-211 in the hematopoietic system, and/or in the development of acute myeloid leukemia (AML) however remains unexplored.

Using microRNA expression profiling, across two independent pediatric AML cohorts, we are the first to identify that miR-211 expression is elevated in a subset of patients, from more than 2-fold and up to 50-fold above non-leukemic remission controls. High expression of miR-211 tends to be clustered in patients with cytogenetically normal and M5 AML subtypes. Using hematopoietic reconstitution experiments in mouse models, we show for the first time that enforced expression of miR-211 alone in hematopoietic stem cells is sufficient to drive a partially-penetrant myeloproliferative disease that phenotypically resembles acute myeloid leukemia. Affected mice have an expansion of immature myeloid cells, expressing CD11b and Gr-1 cell surface markers, with monoblastic cellular morphology. This is accompanied by severe anemia and thrombocytopenia, and dissemination of immature hematopoietic cells into the spleen, liver and extramedullary spaces of the bone marrow. We have also explored the potential co-operation between miR-211 and AML oncogenes. Strikingly, preliminary data suggests miR-211 can co-operate with activating RAS mutations to immortalize cells in vitro, and drive AML in vivo .

To further explore the molecular mechanisms of miR-211 in AML, we used RNA sequencing and differential expression analysis to compare transcriptional changes induced by miR-211 overexpression in disease mice relative to empty vector controls. We have identified Lin28a as the most downregulated miR-211 gene target. Lin28a is a well-established target of miR-125b in AML and its knockdown leads to an analogous expansion of myeloid cells in vivo as observed in miR-211-dependent AML.

Collectively, our results demonstrate a previously unidentified role for miR-211 as an oncogenic microRNA in the development of AML and suggests that miR-211 may potentially drive the development of AML by blocking myeloid differentiation through the repression of Lin28a .