Mapping cancer micro-environments for acute leukemia

虽然对支持白血病进展的细胞内在因素了解很多， 了解微环境的作用。T细胞急性淋巴细胞白血病（T-ALL）细胞 通常在表面受体的下游途径中获得突变， 分化、存活和增殖对环境线索的反应，并且不知道是否 这样的遗传事件使T-ALL免于依赖于假定的白血病小生境。我们发现T- ALL细胞与产生CXCL 12的骨髓基质直接稳定接触。而且两 CXCL 12受体CXCR 4在鼠疾病模型中的遗传靶向和药理学 人T-ALL异种移植物中的CXCR 4拮抗作用导致快速和持续的疾病缓解。在这里， 我们建议进一步绘制和功能解剖T-ALL的骨髓小生境，并测试T-ALL的骨髓小生境。 靶向T-ALL的潜力：利基相互作用作为这种侵袭性血液的新治疗途径 恶性肿瘤我们将使用标记不同生态位元件的新型遗传报告基因的组合， 涉及T-ALL进展的因子的靶向等位基因-CXCL 12，Notch配体， 和细胞因子IL-7 -来识别维持T-ALL的关键细胞。我们还将使用强大的CXCR 4 拮抗剂和一组充分表征的原代人异种移植物，以测试治疗性 将T-ALL细胞从其小生境中驱逐的可能性。

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.