Mammalian hematopoiesis is regulated by a complex network of genes that include both microRNAs (miRNAs) and transcription factors. miRNAs are small, 18-22 nucleotide non-coding RNAs that inhibit protein expression by targeting specific sequences in the 3'untranslated region (UTR) of their mRNA targets. We have recently demonstrated that ectopic over-expression of miRNA-125b in the bone marrow compartment of WT C57BL/6 mice causes an aggressive myeloid leukemia with increased numbers of myeloid progenitors and mature cells. Importantly, we have shown that IRF4, a tumor suppressor in myeloid cells, is a definitive target of miRNA-125b. IRF4 binds to MyD88, an adaptor protein in the NF-kB signaling pathway, to inhibit NF-kB activation. Consistent with this, ectopic over-expression of miRNA-125b or shRNA mediated knock-down of IRF4 can both lead to basal activation of macrophages and potentiation of their function. The objective of this work is to elucidate the molecular mechanism of miRNA-125b mediated myeloid disease. We hypothesize that miRNA-125b causes an aggressive myeloid disease by negatively regulating expression of IRF4, a negative regulator of NF-kB signaling.
In Aim 1, we further characterize the role of miRNA-125b in myeloid development and leukemia, with an emphasis on determining the cellular mechanism of disease.
In Aim 2. 1, we will investigate the contribution of IRF4 to the miRNA-125b mediated leukemic phenotype. Finally, in Aim 2.2, we will study the importance of NF-kB signaling in increasing myeloid output and causing leukemia with miRNA-125b over-expression. Overall, we hope to understand the function of miRNA-125b, which is deregulated in several human cancers, in hematopoiesis in a relevant in vivo system. Importantly, we will also elucidate a set of basic principles on how a miRNA can alter the balance between normal and aberrant hematopoiesis.
This project will elucidate the role of microRNA-125b in the regulation of myeloid development and disease, including the mechanism by which microRNA-125b can tip the balance between normal and aberrant hematopoietic output. This project is especially relevant to public health because microRNA-125b is up- regulated in several forms of leukemia, including acute myeloid leukemia, chronic myeloid leukemia, and many more. Understanding the mechanism by which microRNA-125b causes leukemic development may help us identify other potentially novel targets as critical contributors to developmental defects n myeloid cells. Furthermore, the project will uncover a set of principles by which microRNAs can affect the timing and output of developmental processes. Understanding these principles can shed insight into how deregulation of microRNAs might lead to other, non-hematopoietic cancers.
|Mehta, Arnav; Zhao, Jimmy L; Sinha, Nikita et al. (2015) The MicroRNA-132 and MicroRNA-212 Cluster Regulates Hematopoietic Stem Cell Maintenance and Survival with Age by Buffering FOXO3 Expression. Immunity 42:1021-32|
|Mehta, Arnav; Mann, Mati; Zhao, Jimmy L et al. (2015) The microRNA-212/132 cluster regulates B cell development by targeting Sox4. J Exp Med 212:1679-92|