Role of Secreted frizzled-related Protein 1 (Sfrp 1) in the function of the hematopoietic niche

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Hematopoietic stem cells (HSCs) reside in a specific niche within the bone marrow that is critical for maintaining these cells under steady state and stress conditions. We have shown that HSCs and stromal cells interact, whereby the niche is stimulated to produce factors which prevent HSC senescence and exhaustion. Interestingly, knockdown of secreted frizzled-related protein 1 (Sfrp1) causes senescence of stromal cells, which do not properly maintain HSCs. Interestingly, downregulation of Sfrp1 activates stromal p53 and its targets. In this research proposal, we will exploit stromal cells in which expression of Sfrp1 is knocked down and identify key nodes in the p53 pathway determining the niche signals regulating HSCs using gene editing. We further aim to dissect the mechanisms of HSC dysregulation in vivo using a conditional Sfrp1flox/flox deletion model generated in the lab. Preliminary experiments in Osx-Cre-driven Sfrp1 deletion mutants show that stromal cells from these mice express markers of senescence. Thus, we will investigate the role of niche senescence and the involvement of p53 and its targets in HSC regulation in vivo, and also determine whether p53 inhibition rescues the defective hematopoiesis in Sfrp1-deficient animals. In the second part of this project, the niche dependence of BCR-ABL+ leukemic cells will be investigated. We found that the Sfrp1-deficient environment forms leukemic cells with different self- renewal and cell fate decisions than those formed in a WT environment. Here, we will assess whether and how defective niche function in the Sfrp1-deficient environment determines alterations in leukemogenesis on a clonal level, and whether this affects therapeutic success. Thus, we will identify key Sfrp1- and p53-dependent pathways involved in niche function and how those regulate HSC and leukemia.