(PLEASE KEEP IN WORD, DO NOT PDF) (Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text.) It has been reported that depletion of RUNX21 or LepR2 in mesenchymal stem/progenitor cells (MSPCs) reduces bone mass and increases bone marrow (BM) adipocytes (BMA), and that PDGFRβ activation drives MSPC expansion and BM vasculogenesis, finally influencing hematopoiesis3. Our preliminary data show that mice lacking SHP2 in the Osterix+ stromal progenitor cells (O+SPCs) have similarly increased BMA and BM vasculature and skewed lymphopoiesis. We have not yet determined the molecular mechanism(s) by which SHP2 exerts its influence on O+SPCs and hematopoietic cells. However, the phenotypic similarity of mice lacking SHP2, RUNX2, LepR, or PDGFR in O+SPCs leads us to hypothesize that SHP2 influences the osteogenic, adipogenic and/or stromogenic fate of O+SPCs by modifying the transcription activity of RUNX2 and the kinase activity of PDGFR, and that altered BM O+SPCs change the cellular and molecular constituents of the BM niche and subsequently hematopoiesis. To test this novel hypothesis, we will complete two specific aims. In Aim 1 we will interrogate the impact of SHP2 depletion on RUNX2 transcriptional activity in O+SPCs, while in Aim 2 we will determine the effect of SHP2 depletion on stromogenic differentiation of O+SPCs and hematopoisis in vitro and in vivo. O+SPCs participate in BM hematopoietic niche construction and maintenance, and both SHP2 and RUNX2 influence O+SPCs. This innovative study will yield foundational information regarding SHP2’s regulatory role in O+SPCs and its consequent role in hematopoiesis and BM vasculogenesis. This information will significantly advance our understanding of the effect and importance of crosstalk between BM stromal cells and hematopoietic cells, and hematopoietic malignancy.

SHP2 mutations are associated with several hematopoietic disorders, to which the underlying molecular and cellular mechanism remains elusive. Understanding how BM mesenchymal niches and BM vasculature are regulated by SHP2 and RUNX2 will greatly advance our knowledge regarding hematopoiesis regulation and it will be instrumental to the development of novel therapeutics. References 1 Tosa, I. et al. Postnatal Runx2 deletion leads to low bone mass and adipocyte accumulation in mice bone tissues. Biochem Biophys Res Commun 516, 1229-1233 (2019). https://doi.org:10.1016/j.bbrc.2019.07.014 2 Yue, R., Zhou, B. O., Shimada, I. S., Zhao, Z. & Morrison, S. J. Leptin Receptor Promotes Adipogenesis and Reduces Osteogenesis by Regulating Mesenchymal Stromal Cells in Adult Bone Marrow. Cell Stem Cell 18, 782-796 (2016). https://doi.org:10.1016/j.stem.2016.02.015 3 Bohm, A. M. et al. Activation of Skeletal Stem and Progenitor Cells for Bone Regeneration Is Driven by PDGFRbeta Signaling. 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