Role of the non-canonical Wnt regulator Wnt5a in normal and malignant hematopoiesis

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Prominent players in the regulation of self-renewal and differentiation are Wnt-signaling members. We found that non-canonical Wnt5a in the microenvironment is required for self-renewal of hematopoietic stem cells (HSCs) after regeneration. Loss of self-renewal is associated with increased calcium-dependent signaling and homing deficiencies. Interestingly, the loss of self-renewal is not restricted to normal HSCs. Indeed, p185 Bcr-Abl fails to establish full leukemic transformation, and a population of leukemia-initiating cells capable of propagating disease in secondary transplants does not develop. Although these findings correlate with changes in the distribution of niche cell subpopulations, it is unclear whether the characteristic inflammatory phenotype of leukemic niche cells can be established in a Wnt5a-deficient microenvironment. Here, we will investigate possible mechanisms through which self-renewal and leukemia development is impaired in Wnt5a-deficient environment. For this purpose, we will employ gene and protein expression studies, genetic manipulation of HSCs and niche cells, and functional studies in vitro and in vivo. Furthermore, our results strongly suggest that non-canonical Wnt signaling is a therapeutic target in Bcr-Abl+ leukemia. Thus, we propose to study inhibitors of both calcium-dependent and planar cell polarity Wnt pathways as therapeutic targets on their own, or in combination with the Bcr-Abl inhibitor imatinib. In addition, we will dissect different niche populations in WT and Wnt5a+/- mice to find out whether a functional leukemia supportive niche is recruited. These studies will be complemented with experiments using mice in which Wnt5a is conditionally knocked out in specific cell populations, such as in Osx-Cre::Wnt5a-fl/fl mice. Our studies aim to definitively elucidate the mechanisms through which non-canonical Wnt5a-signaling contributes to HSC self-renewal and establishment of leukemia-initiating cells and recruitment of a leukemic niche.