Uncoupling of Jak/STAT in HTLV-1 associated leukemia

描述(申请人提供)：HTLV-I感染与一种侵袭性和致命性T细胞白血病/淋巴瘤有关，被指定为成人T细胞白血病/淋巴瘤(ATLL)。从HTLV-I永生化T细胞向HTLV-I转化T细胞的转变与JAK/STAT信号通路的结构性激活以及酪氨酸磷酸酶-1(SHP-1)表达水平的降低有关。在ATLL的早期阶段，病毒蛋白Tax和Rex参与了IL-2和IL-2R的上调表达，并可能参与了感染细胞的自分泌增殖。虽然目前尚不确定在ATLL的晚期，这些蛋白的表达水平仍然足以维持IL-2/IL-2R途径的激活。ATLL肿瘤细胞持续表达高水平的IL-2Rα链，并表现出结构性的JAK/STAT激活。IL-2/IL-2R信号通路对ATIL细胞的持续增殖和小鼠肿瘤的形成至关重要。因为STAT蛋白是有效的抗凋亡蛋白的诱导者，干扰HTLV-L介导的JAK/STAT活化可以在白血病细胞中触发凋亡信号。我们先前已经证明病毒蛋白HTLV-I p12与IL-2Rβ和伽马链相互作用，导致STAT5依赖的转录增加，并提出p12在成人T细胞白血病的发病机制中起重要作用。在第一个目标中，我们将鉴定和突变p12与IL-2Rβ和伽马链结合的区域，并研究它们在人原代T细胞体外JAK/STAT激活和转化中的意义。由于HTLV-II不激活Jak/STAT通路，因此将构建HTVL-I和HTVL-II之间的p12嵌合体进行互补分析。在第二个目的中，我们将研究细胞因子信号转导抑制物SOCS、CIS和SHP-1在p12和p12-HTLV-I永生化细胞和HTLV-I感染患者样本中的表达。我们将研究JAK/STAT激活的分子机制及其在肿瘤细胞存活和端粒酶活性中的作用。在第三个目标中，我们将研究p12介导的IL-2/IL-2R和JAK/STAT通路在端粒酶激活和长期细胞增殖中的作用。我们还将描述p12如何促进肿瘤细胞中的抗凋亡信号。这些研究的结果将影响我们对Jak/STAT信号转导途径失控相关发病机制的理解，并可能为人类T细胞白血病和淋巴瘤的治疗提供新的治疗靶点。

DESCRIPTION (provided by applicant): HTLV-I infection is epidemiologically associated with an aggressive and fatal T-cell leukemia/lymphoma designated as Adult T-cell leukemia/lymphoma (ATLL). The transition from HTLV-I immortalized to HTLV-I transformed T cells has been associated with constitutive activation of the Jak/STAT signaling pathways as well as with a reduction of level of the tyrosine phosphatase-1 (SHP-1) expression. In early stages of ATLL viral proteins Tax and Rex are involved in up-regulated expression if IL-2 and IL-2R and possibly autocrine proliferation of infected cells. Although it is uncertain that in late stages of ATLL these proteins are still expressed in sufficient levels to maintain activation of the IL-2/IL-2R pathway. ATLL tumor cells consistently express high levels of IL-2R alpha chain and display constitutive Jak/STAT activation. IL-2/IL-2R signaling pathway is critical for continuous proliferation of ATLL cells and tumor formation in a mouse model. Because STAT proteins are potent inducers of anti-apoptotic proteins; interfering with HTLV-l-mediated Jak/STAT activation could trigger an apoptotic signal in leukemic cells. We have previously demonstrated that the viral protein HTLV-I p12 interacts with IL-2R beta and gamma chains leading to increase in STAT5-dependent transcription and propose that p12 plays an essential role in pathogenesis of adult T-cell leukemia. In the first aim we will identify and mutate the regions of p12 involved in binding to IL-2R beta and gamma chains and study their implication in Jak/STAT activation and transformation of human primary T-cells in vitro. Because HTLV-II does not activate Jak/STAT pathway, p12 chimera between HTVL-I and II will be constructed for complementation assays. In the second aim we will study expression of suppressors of cytokine signaling SOCS, CIS, and SHP-1 in p12+ and p12- HTLV-I immortalized cells and HTLV-I infected patient samples. We will investigate molecular mechanisms underlying Jak/STAT activation and its role in survival and telomerase activity of tumor cells. In the third aim we will study the role of p12-mediated activation of the IL- 2/IL-2R and Jak/STAT pathways in telomerase activation and long term cell proliferation. We will also characterize how p12 promote anti apoptotic signals in tumor cells. Results from these studies will impact our understanding of pathogenesis associated with deregulated Jak/STAT pathway and may reveal new therapeutic targets for the treatment of human T-cell leukemias and lymphomas.