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首页> 外文期刊>Molecular and Cellular Endocrinology >JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics
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JAK/STAT pathway directed therapy of T-cell leukemia/lymphoma: Inspired by functional and structural genomics

机译：T细胞白血病/淋巴瘤的jak / stat途径定向治疗：受功能性和结构基因组学的启发

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摘要

Abnormal activation of the gamma c cytokine JAR/STAT signaling pathway assessed by STAT3 or STAT5b phosphorylation was present in a proportion of many T-cell malignancies. Activating mutations of STAT3/STAT5b and JAK1/3 were present in some but not in all cases with constitutive signaling pathway activation. Using shRNA analysis pSTAT malignant T-cell lines were addicted to JAKs/STATs whether they were mutated or not. Activating JAR/STAT mutations were not sufficient to support leukemic cell proliferation but only augmented upstream pathway signals. Functional cytokine receptors were required for pSTAT expression. Combining a JAK1/2 inhibitor with a Bcl-xL inhibitor navitoclax provided additive/synergistic activity with IL-2 dependent ATLL cell lines and in a mouse model of human IL-2 dependent ATLL. The insight that disorders of the yc/JAK/STAT system are pervasive suggests approaches including those that target gamma cytokines, their receptors or that use JAR kinase inhibitors may be of value in multicomponent therapy for T-cell malignancies. Published by Elsevier Ireland Ltd.
机译：通过STAT3或Stat5B磷酸化评估的γC细胞因子蛋筒/统计信令途径的异常活化以许多T细胞恶性肿瘤的比例存在。在某些情况下存在STAT3 / Stat5B和JAK1 / 3的激活突变，但在所有具有组成型信号通路活化的情况下存在。使用ShRNA分析，Pstat恶性T细胞系沉迷于jaks / stats是否被突变。激活罐/统计突变不足以支持白血病细胞增殖，而是仅增强上游路径信号。 Pstat表达需要功能性细胞因子受体。将JAK1 / 2抑制剂与BCL-XL抑制剂Navitoclax组合提供添加/协同活性与IL-2依赖性ATLL细胞系和人IL-2依赖于ATL1的小鼠模型。 YC / JAK / STAT系统的疾病普及的洞察力表明包括靶向γ细胞因子，它们的受体或使用JAR激酶抑制剂的方法的方法可能对T细胞恶性肿瘤的多组分治疗有价值。 elsevier爱尔兰有限公司出版

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