JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model
JAK3 mutants transform hematopoietic cells through JAK1 activation, causing T-cell acute lymphoblastic leukemia in a mouse model
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DOI：
10.1182/blood-2014-04-566687
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发表时间：
2014-11-13
期刊：
影响因子：
20.3
通讯作者：
Cools, Jan
中科院分区：
文献类型：
--
作者：
Degryse, Sandrine;de Bock, Charles E.;Cools, Jan
JAK3 是一种酪氨酸激酶，与细胞因子受体的常见 γ 链相关，并在 T 细胞急性淋巴细胞白血病 (T-ALL) 中反复突变。我们使用体外和体内测定测试了 JAK3 假激酶和激酶结构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 假激酶突变体依赖于 Jak1 激酶活性进行细胞转化，而 JAK3 激酶结构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一种长潜伏期的可移植性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布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。我们的数据表明，JAK3 突变是 T-ALL 的驱动因素，并且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用于治疗 T-ALL 的 JAK1/JAK3 抑制剂。
JAK3 is a tyrosine kinase that associates with the common gamma 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.