JAK3 突变体通过 JAK1 激活转化造血细胞，导致小鼠模型中的 T 细胞急性淋巴细胞白血病,Blood

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JAK3 突变体通过 JAK1 激活转化造血细胞，导致小鼠模型中的 T 细胞急性淋巴细胞白血病
Blood ( IF 21.0 ) Pub Date : 2014-11-13 , DOI: 10.1182/blood-2014-04-566687
Sandrine Degryse ₁ , Charles E de Bock ₁ , Luk Cox ₁ , Sofie Demeyer ₁ , Olga Gielen ₁ , Nicole Mentens ₁ , Kris Jacobs ₁ , Ellen Geerdens ₁ , Valentina Gianfelici ₂ , Gert Hulselmans ₃ , Mark Fiers ₁ , Stein Aerts ₃ , Jules P Meijerink ₄ , Thomas Tousseyn ₅ , Jan Cools ₁

Affiliation

JAK3 是一种酪氨酸激酶，与细胞因子受体的共同 γ 链相关联，并在 T 细胞急性淋巴细胞白血病 (T-ALL) 中反复发生突变。我们使用体外和体内试验测试了 JAK3 假激酶和激酶域突变体的转化特性。大多数（但不是全部）JAK3 突变体将细胞因子依赖性 Ba/F3 或 MOHITO 细胞系转化为细胞因子非依赖性增殖。JAK3 假激酶突变体依赖 Jak1 激酶活性进行细胞转化，而 JAK3 激酶域突变体可以以不依赖 Jak1 激酶的方式转化细胞。293T 细胞中 IL7 受体信号复合物的重建表明 JAK3 突变体需要受体结合来介导下游 STAT5 磷酸化。移植了表达 JAK3 突变体的骨髓祖细胞的小鼠出现了长延迟可移植 T-ALL 样疾病，其特征是未成熟 CD8(+) T 细胞的积累。用 JAK3 选择性抑制剂托法替尼对白血病小鼠进行体内治疗，可减少白细胞计数并导致白血病细胞凋亡。我们的数据显示 JAK3 突变是 T-ALL 的驱动因素，需要细胞因子受体复合物进行转化。这些结果值得进一步研究 JAK1/JAK3 抑制剂治疗 T-ALL。我们的数据显示 JAK3 突变是 T-ALL 的驱动因素，需要细胞因子受体复合物进行转化。这些结果值得进一步研究 JAK1/JAK3 抑制剂治疗 T-ALL。我们的数据显示 JAK3 突变是 T-ALL 的驱动因素，需要细胞因子受体复合物进行转化。这些结果值得进一步研究 JAK1/JAK3 抑制剂治疗 T-ALL。

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JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model

JAK3 is a tyrosine kinase that associates with the common γ chain of cytokine receptors and is recurrently mutated in T-cell acute lymphoblastic leukemia (T-ALL). We tested the transforming properties of JAK3 pseudokinase and kinase domain mutants using in vitro and in vivo assays. Most, but not all, JAK3 mutants transformed cytokine-dependent Ba/F3 or MOHITO cell lines to cytokine-independent proliferation. JAK3 pseudokinase mutants were dependent on Jak1 kinase activity for cellular transformation, whereas the JAK3 kinase domain mutant could transform cells in a Jak1 kinase-independent manner. Reconstitution of the IL7 receptor signaling complex in 293T cells showed that JAK3 mutants required receptor binding to mediate downstream STAT5 phosphorylation. Mice transplanted with bone marrow progenitor cells expressing JAK3 mutants developed a long-latency transplantable T-ALL-like disease, characterized by an accumulation of immature CD8(+) T cells. In vivo treatment of leukemic mice with the JAK3 selective inhibitor tofacitinib reduced the white blood cell count and caused leukemic cell apoptosis. Our data show that JAK3 mutations are drivers of T-ALL and require the cytokine receptor complex for transformation. These results warrant further investigation of JAK1/JAK3 inhibitors for the treatment of T-ALL.

更新日期：2014-11-13

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