Uncoupling of Jak/STAT in HTLV-1 associated leukemia

HTLV-1 相关白血病中 Jak/STAT 的解偶联

• 批准号: 7915825
• 负责人: CHRISTOPHE P NICOT
• 金额: $ 20.64万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915825
• 关键词: Acute; Adult; Apoptotic; Binding; Binding Sites; Biological Assay; Cell Line; Cell Proliferation; Cells; Cessation of life; Chimera organism; Chronic; Collaborations; Cytokine Inducible SH2-Containing Protein; Data; Gene Mutation; Genetic; Genetic Transcription; Goals; Hematological Disease; Homologous Gene; Human; Human T-lymphotropic virus 1; Human T-lymphotropic virus 2; IL2RA gene; In Vitro; Individual; Infection; Interleukin-2; Interruption; Knock-out; Letters; Leukemic Cell; Maps; Mediating; Membrane Microdomains; Modeling; Molecular; Molecular Cloning; Mutate; NR0B2 gene; Oryctolagus cuniculus; PTPN6 gene; Pathogenesis; Pathway interactions; Patients; Phenotype; Play; Process; Protein Dephosphorylation; Protein Tyrosine Phosphatase; Proteins; Proviruses; Research Personnel; Reticulocytes; Risk; Role; STAT protein; Sampling; Series; Signal Pathway; Signal Transduction; Staging; T-Cell Leukemia; T-Cell Transformation; T-Lymphocyte; Taxes; Telomerase; Testing; United States; Viral; Viral Genes; Viral Proteins; Virus Replication; autocrine; cell transformation; cell type; immortalized cell; in vitro testing; in vivo; leukemia; leukemia/lymphoma; mouse model; mutant; neoplastic cell; new therapeutic target; programs; reconstitution; research study; vector

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.

描述（由申请方提供）：HTLV-I感染在流行病学上与侵袭性和致死性T细胞白血病/淋巴瘤相关，称为成人T细胞白血病/淋巴瘤（ATLL）。从HTLV-I永生化T细胞到HTLV-I转化T细胞的转变与Jak/STAT信号传导途径的组成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和雷克斯参与IL-2和IL-2 R的上调表达以及可能的感染细胞的自分泌增殖。尽管尚不确定在ATLL的晚期阶段，这些蛋白质是否仍以足够的水平表达以维持IL-2/IL-2 R途径的激活。ATLL肿瘤细胞始终表达高水平的IL-2 R α链并显示组成性Jak/STAT活化。IL-2/IL-2 R信号通路对小鼠模型中ATLL细胞的持续增殖和肿瘤形成至关重要。因为STAT蛋白是抗凋亡蛋白的有效诱导剂;干扰HTLV-1介导的Jak/STAT活化可在白血病细胞中触发凋亡信号。我们以前已经证明，病毒蛋白HTLV-I p12与IL-2 R β和γ链相互作用，导致STAT 5依赖性转录增加，并提出p12在成人T细胞白血病的发病机制中起着重要作用。在第一个目标中，我们将鉴定和突变参与结合IL-2 R β和γ链的p12区域，并研究它们在体外人原代T细胞的Jak/STAT活化和转化中的意义。由于HTLV-II不激活Jak/STAT通路，因此将构建HTVL-I和II之间的p12嵌合体用于互补测定。在第二个目标中，我们将研究细胞因子信号传导抑制因子SOCS、CIS和SHP-1在p12+和p12- HTLV-I永生化细胞和HTLV-I感染的患者样品中的表达。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-2 R和Jak/STAT通路的激活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与Jak/STAT途径失调相关的发病机制的理解，并可能揭示治疗人类T细胞白血病和淋巴瘤的新治疗靶点。