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（由申请人提供）：HTLV-I感染在流行病学上与被指定为成人T细胞白血病/淋巴瘤（ATLL）的侵略性和致命的T细胞白血病/淋巴瘤相关。从永生的HTLV-I向HTLV-I转化的T细胞的过渡与JAK/STAT信号途径的组成型激活以及酪氨酸磷酸酶-1（SHP-1）表达水平的降低有关。如果IL-2和IL-2R以及可能是感染细胞的自分泌增殖，则在ATLL病毒蛋白的早期阶段参与上调的表达。尽管尚不确定在ATLL的后期阶段，这些蛋白质仍以足够的水平表达以保持IL-2/IL-2R途径的激活。 ATLL肿瘤细胞始终表达高水平的IL-2Rα链，并显示构型JAK/Stat激活。 IL-2/IL-2R信号通路对于小鼠模型中ATLL细胞和肿瘤形成的连续增殖至关重要。因为Stat蛋白是抗凋亡蛋白的有效诱导剂；干扰HTLV-L介导的JAK/Stat激活可能会触发白血病细胞中的凋亡信号。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依赖性转录的增加，并提出p12在成人T细胞白血病的发病机理中起着至关重要的作用。在第一个目的中，我们将识别和突变与IL-2Rβ和伽马链结合的p12区域，并研究它们在JAK/Stat激活和体外人类原代T细胞转化中的影响。由于HTLV-II不会激活JAK/STAT途径，因此将构建HTVL-I和II之间的p12嵌合体进行补充测定。在第二个目标中，我们将研究p12+和p12-HTLV-I永生细胞以及HTLV-I感染的患者样品中细胞因子信号SOC，顺式和SHP-1抑制器的表达。我们将研究JAK/Stat激活的基础机制及其在肿瘤细胞的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途径在端粒酶激活和长期细胞增殖中的激活的作用。我们还将表征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失控的JAK/STAT途径相关的发病机理的理解，并可能揭示用于治疗人类T细胞白血病和淋巴瘤的新治疗靶标。