While much is known about the cell-intrinsic factors that support leukemia progression, little is understood about the role of the microenvironment. T cell acute lymphoblastic leukemia (T-ALL) cells have commonly acquired mutations in pathways downstream of surface receptors that regulate differentiation, survival and proliferation in response to environmental cues, and it is unknown whether such genetic events free T-ALL from dependence on a putative leukemic niche. We have found that T- ALL cells are in direct, stable contact with CXCL12-producing bone marrow stroma. Moreover, both genetic targeting of the CXCL12 receptor CXCR4 in murine disease models and pharmacologic CXCR4 antagonism in human T-ALL xenografts led to rapid and sustained disease remission. Here, we propose to further map and functionally dissect the bone marrow niche for T-ALL, and test the potential of targeting T-ALL:niche interactions as a novel therapeutic avenue for this aggressive blood malignancy. We will use a combination of novel genetic reporters marking distinct niche elements and targeted alleles of factors that have been implicated in T-ALL progression ? CXCL12, Notch ligands, and the cytokine IL-7 ? to identify the key cells that maintain T-ALL. We will also use a potent CXCR4 antagonist and a panel of well-characterized primary human xenografts to test the therapeutic potential of dislodging T-ALL cells from their niches.
In this application we will map T cell acute leukemia niches in the bone marrow, and test the potential of targeting leukemia's interaction with the microenvironment as a novel therapeutic avenue for this aggressive blood malignancy.
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