At the root of the hematopoietic system are long-term hematopoietic stem cells (LT-HSCs), an exceedingly rare population of multi-potent cells capable of self-renewal. Hematopoietic differentiation is accomplished through stably propagated changes to gene expression that are mediated by epigenetic factors, such as DNA methylation and chromatin remodeling, and the expression of microRNAs. Mutation and dysregulation of epigenetic effector genes, such as TET2 and DNMT3a, and aberrant microRNA expression have been implicated in hematological malignancies. Myelodysplastic syndrome (MDS) is an incurable stem cell disorder that is characterized by ineffective hematopoiesis and a risk of transformation to myeloid leukemia, and is frequently associated with abnormal DNA methylation. TET2, or tet methylcytosine dioxygenase 2, oxidizes the repressive 5-methylcytosine (5-mC) mark to 5-hydroxymethylcytosine (5-hmC), the first step in removing DNA methylation. microRNA-22 (miR-22) is highly expressed in MDS and is associated with poor survival rates. In mice, miR-22 over-expression reduces global 5-hmC through repression of its target, Tet2, increases the self-renewal capacity of HSCs, and results in the development of an MDS-like disease. Using recent advances in the ability to profile genome-wide cytosine hydroxymethylation, we seek to identify specific targets of the miR-22/TET2 regulatory network in HSCs that contribute to the development of MDS. We also aim to describe miR-22's role as a mediator of normal hematopoiesis using a novel reporter of miR-22 expression. Finally, we aim to identify the potential for the inhibition of miR-22 in the treatment of MDS using recently acquired miR-22 knockout mice. The successful completion of this work will provide essential insights into the roles of microRNAs and epigenetic changes in the regulation of hematopoietic stem cell fate and the pathogenesis of hematological diseases, and may ultimately impact the treatment of poor-prognosis MDS.
Myelodysplastic Syndrome (MDS) is a group of incurable hematopoietic stem cell disorders that are characterized by a failure in the maturation of blood cells, which contributes to anemia and multi-lineage dysplasia, and can progress to the development of acute myeloid leukemia. Recently, microRNAs and epigenetic regulators have been implicated in the pathogenesis of MDS. The goal of this project is to elucidate the role of the microRNA-22/TET2 regulatory network in the progression of MDS by understanding the network's contribution to hematopoiesis, identifying targets of the regulatory network that worsen the prognosis of MDS, and to explore the safety and efficacy of inhibiting the microRNA-22/TET2 network in the treatment of MDS.
| Weiss, Cary N; Ito, Keisuke (2017) A Macro View of MicroRNAs: The Discovery of MicroRNAs and Their Role in Hematopoiesis and Hematologic Disease. Int Rev Cell Mol Biol 334:99-175 |
