Epigenetic silencing of SOCS5 potentiates JAK-STAT signaling and progression of T-cell acute lymphoblastic leukemia
Epigenetic silencing of SOCS5 potentiates JAK-STAT signaling and progression of T-cell acute lymphoblastic leukemia
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DOI：
10.1111/cas.14021
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发表时间：
2019-06-01
期刊：
影响因子：
5.7
通讯作者：
Matlawska-Wasowska, Ksenia
中科院分区：
文献类型：
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作者：
Sharma, Nitesh D.;Nickl, Christian K.;Matlawska-Wasowska, Ksenia
细胞因子受体和转录调节因子的激活突变控制T细胞系急性淋巴细胞白血病（T-ALL）的异常信号转导。然而，细胞因子信号转导抑制因子所起的作用仍不完全清楚。我们研究了细胞因子信号抑制因子5（SOCS 5）在T-ALL细胞信号网络和白血病进展中的调节作用。我们发现SOCS 5在原发性T-ALL中差异表达，其表达水平在HOXA失调的白血病中降低，携带KMT 2A基因重排。在这里，我们报告SOCS 5的表达是由DNA甲基转移酶-3A介导的DNA甲基化和甲基CpG结合蛋白-2介导的组蛋白去乙酰化的表观遗传调控。我们发现SOCS 5负调控T-ALL细胞生长和细胞周期进程，但对凋亡细胞死亡没有影响。从机制上讲，SOCS 5沉默诱导JAK-STAT信号转导的激活，并负调节白细胞介素-7和白细胞介素-4受体。使用人T-ALL小鼠异种移植模型，我们表明SOCS 5的遗传失活加速白血病植入和进展，以及白血病负荷。我们推测SOCS 5在T-ALL中是表观遗传失调的，并且是T-ALL细胞增殖和白血病进展的重要调节因子。我们的研究结果将SOCS 5表达的异常下调与T-ALL中JAK-STAT和细胞因子受体信号级联的增强激活联系起来。
Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.