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 with distinct microRNA signatures associated with cancers of different tissues, subtypes of the disease and as predictors of patient outcome. A subset of microRNAs also has well-established roles as drivers of cancer development and is a potential therapeutic target. In a model of induced expression of an oncogene in primary murine myeloid cells, we recently identified 70 microRNAs that were differentially expressed in the presence and absence of the oncogene. This raised the hypothesis that at least some of these microRNAs have roles in the regulation of myeloid differentiation and in the development of myeloid leukemia. MicroRNA-211 (miR-211) was the most differentially expressed microRNAs in this model, and is the focus of the work presented here.
MiR-211 is an intronic microRNA encoded on human chromosome 15 and deregulated miR-211 expression has been previously described in melanoma and other cancers. The role of miR-211 in hematological malignancies, however, is unknown. Using hematopoietic reconstitution experiments in mouse models, our data shows for the first time that enforced expression of miR-211 in hematopoietic stem cells drives a partially penetrant myeloid disease, characterized by an increased proportion of immature myeloid cells in their bone marrow and spleen, with monoblastic cellular morphology. This is accompanied by severe anemia, thrombocytopenia, and infiltration of immature hematopoietic cells into the peripheral hematopoietic tissues, phenotypically resembling acute myeloid leukemia (AML). Additionally, RNA sequencing analysis of molecular targets of miR-211 in AML suggests that miR-211 potentially mediates disease by regulating the RAS oncogenic pathway. Most interestingly, preliminary data from a cohort of paediatric leukemic patients showed that elevated expression of miR-211 is detected in a subset of patients with monoblastic (M5) acute myeloid leukemia, suggesting miR-211 may have a previously unidentified role in AML.