BNMC Seminar:  The impact of miRNAs on hematopoietic development, function and disease

Ryan O'Connell
Post-doctoral Scholar
Biology
Caltech

Mammalian microRNAs (miRNAs) are emerging as key regulators of the development and function of the immune system, representing a novel layer of gene expression regulation. However, little is known regarding the role of miRNAs during inflammatory responses to infection. We have found that primary macrophages specifically upregulate miR-155 to high levels following exposure to a variety of microbial products and inflammatory cytokines. Strong but transient induction of miR-155 was also observed in mouse bone marrow after injection of bacterial LPS correlated with GM expansion. To test the functional consequences of miR-155 expression in the hematopoietic system, miR-155 expression was enforced in the bone marrow using retroviral-mediated gene transfer. Mir-155 expressing mice exhibited a profound myeloproliferative phenotype, characterized by granulocyte/monocyte (GM) expansion along with defects in several other cell lineages. Of note, the miR-155-induced GM populations displayed pathological features characteristic of myeloid neoplasia. Extending possible relevance to human disease, miR-155 was overexpressed in the bone marrow of patients with acute myeloid leukemia (AML). Finally, miR-155 repressed a subset of genes implicated in hematopoietic development and disease, suggesting a mechanistic basis for miR-155 function. These data implicate miR-155 as a contributor to physiological GM expansion during inflammation and to certain pathological features associated with AML, emphasizing the importance of proper miR-155 regulation in developing myeloid cells during times of inflammatory stress.