Hematopoietic stem cell (HSC) numbers are carefully maintained by switching from symmetric to asymmetric cell divisions. A complex program made of genetic and epigenetic mechanisms that maintain normal HSCs can become dysregulated in hematopoietic disorders and malignancies. Myelodysplastic syndromes (MDS) are characterized as a clonally derived set of heterogeneous diseases demonstrating defective hematopoietic differentiation. Taken together with recent discoveries in the genetic landscape of MDS, the etiology of this disease is considered to be driven by an HSC or an early myeloid progenitor. Thus, dysregulation of cell fate decisions including the balance of asymmetric and symmetric cell division could explain how certain lineages are blocked or why self-renewal is altered. RNA binding proteins in the Msi family have been shown to be important for the switch between symmetric and asymmetric cell division in germ and tissue stem cell function, neural cell differentiation and cell fate determination. Recent studies have implicated MSI2 as a regulator of HSC function and this proposal utilizes Msi2 conditional knockouts and gain of function approaches to dissect the precise role for MSI2 in controlling asymmetric division, self-renewal and cell fate determination. Moreover, this proposal incorporates high throughput sequencing UV-crosslinking immunoprecipitation to identify global RNA targets (HITS-CLIP) that will be used to elucidate the direct mechanism for MSI2 in hematopoietic cells. Furthermore, our global genetic approaches have already uncovered how regulation of translation alters several developmental pathways. MSI2 has also been recently shown to be dysregulated in MDS within """"""""low- risk"""""""" patients, expressing below normal levels and within """"""""high-risk"""""""" patients demonstrating elevated MSI2 expression. This proposal utilizes the NUP98-HOXD13 MDS murine model combined with novel gain and loss of function MSI2 mouse models to study the initial stages of MDS within the HSC. We suggest that MSI2 dysregulation contributes to the biology of hematopoietic disorders and thus a deeper understanding of these mechanisms will provide additional therapeutic approaches.
Understanding how adult blood stem cells maintain themselves is essential for developing future cellular therapies and treating blood diseases including anemias, myelodysplastic disorders and hematopoietic malignancies. Recently, we have uncovered a novel regulator for blood stem cells called MSI2 that is an essential controller of adult blood stem cell fate decisions. This proposal studies the mechanism of action of MSI2 by utilizing genetic mouse models for the development of novel future therapeutic interventions.
|Jee, David; Yang, Jr-Shiuan; Park, Sun-Mi et al. (2018) Dual Strategies for Argonaute2-Mediated Biogenesis of Erythroid miRNAs Underlie Conserved Requirements for Slicing in Mammals. Mol Cell 69:265-278.e6|
|Kharas, Michael G; Lengner, Christopher J (2017) Stem Cells, Cancer, and MUSASHI in Blood and Guts. Trends Cancer 3:347-356|
|Kotini, Andriana G; Chang, Chan-Jung; Chow, Arthur et al. (2017) Stage-Specific Human Induced Pluripotent Stem Cells Map the Progression of Myeloid Transformation to Transplantable Leukemia. Cell Stem Cell 20:315-328.e7|
|Bhagat, Tushar D; Chen, Si; Bartenstein, Matthias et al. (2017) Epigenetically Aberrant Stroma in MDS Propagates Disease via Wnt/?-Catenin Activation. Cancer Res 77:4846-4857|
|Vu, Ly P; Prieto, Camila; Amin, Elianna M et al. (2017) Functional screen of MSI2 interactors identifies an essential role for SYNCRIP in myeloid leukemia stem cells. Nat Genet 49:866-875|
|Yousefi, Maryam; Li, Ning; Nakauka-Ddamba, Angela et al. (2016) Msi RNA-binding proteins control reserve intestinal stem cell quiescence. J Cell Biol 215:401-413|
|Taggart, James; Ho, Tzu-Chieh; Amin, Elianna et al. (2016) MSI2 is required for maintaining activated myelodysplastic syndrome stem cells. Nat Commun 7:10739|
|Park, Sun-Mi; Gönen, Mithat; Vu, Ly et al. (2015) Musashi2 sustains the mixed-lineage leukemia-driven stem cell regulatory program. J Clin Invest 125:1286-98|
|Wang, Shan; Li, Ning; Yousefi, Maryam et al. (2015) Transformation of the intestinal epithelium by the MSI2 RNA-binding protein. Nat Commun 6:6517|