Neoplasia：陈吉龙等免疫细胞癌变的信号通路研究中获新进展

免疫细胞癌变可导致各种白血病/淋巴癌的发生，这些是人类常见的恶性肿瘤。淋巴细胞和粒细胞等由于某些特殊原因发生变异而诱发细胞癌变，其中Bcr-Abl融合癌基因主要诱发了慢性粒细胞白血病（CML）和急性淋巴细胞白血病（ALL）。Bcr-Abl癌蛋白介导细胞癌变的过程涉及多种信号转导通路的分子调控，其中JAK/STAT是关键信号通路之一。SOCS家族蛋白作为细胞因子信号通路的抑制因子，能有效地调节JAK/STAT信号通路，从而维持人体免疫细胞的正常功能和生理平衡。然而，在Bcr-Abl介导的免疫细胞癌变过程中，SOCS蛋白的作用及其调节机制迄今尚不清楚。

中国科学院微生物研究所陈吉龙研究员领导的病毒感染与肿瘤发生机理研究组在前期研究中，揭示了小鼠白血病病毒（携带v-Abl癌基因）感染改变了免疫细胞关键信号通路的活性（Oncogene， 2010， 29：3845-3853）。在此基础上，针对Bcr-Abl癌蛋白如何改变SOCS家族的负调控功能展开研究。通过蛋白质互作和免疫共沉淀等技术，筛选发现了当Bcr-Abl表达时，SOCS-1和SOCS-3具有较高的酪氨酸磷酸化水平，且鉴定其主要的酪氨酸磷酸化位点分别是SOCS-1的Y155和Y204，SOCS-3的Y221。研究合作者、美国Rothman教授研究组在CML病人外周血白细胞中也发现了SOCS-1的酪氨酸磷酸化。陈吉龙研究组通过一系列生物化学、分子生物学以及细胞生物学等实验，证实了Bcr-Abl介导的SOCS-1和SOCS-3酪氨酸磷酸化使其失去了负调节JAK激酶的功能，并在人白血病K562细胞中无法有效地抑制JAK2、STAT5的活性，使BCL-XL蛋白持续表达，从而抑制了细胞的凋亡。应用小鼠致瘤模型，进一步证明了SOCS-1和SOCS-3主要酪氨酸磷酸化位点的突变能显著地抑制Bcr-Abl介导的肿瘤形成及细胞转化。

此项研究揭示了Bcr-Abl癌蛋白通过磷酸化SOCS-1和SOCS-3的酪氨酸残基，使其失去了负调节JAK/STAT信号通路的功能，阐明了Bcr-Abl诱导STAT5持续活化从而促进Bcr-Abl介导免疫细胞癌变的机理。这些研究结果加深了人们对免疫细胞癌变机制的认识，为彻底阐明免疫细胞癌变的信号调控网络提供了帮助。该研究成果已在线发表在国际肿瘤免疫学刊物Neoplasia上。

此项工作得到了国家“973”计划和国家自然科学基金等支持。（生物谷Bioon.com）

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A requirement for SOCS-1 and SOCS-3 phosphorylation in Bcr-Abl-induced tumorigenesis

Xiaoxue Qiu, Guijie Guo, Ke Chen, Masaki Kashiwada, Brian Druker, Paul Rothman and Jilong Chen

SOCS-1 and SOCS-3 are inhibitors of JAK/STAT pathway and function in a negative feedback loop during cytokine signaling. Abl transformation is associated with constitutive activation of JAK/STAT-dependent signaling. However, the mechanism by which Abl oncoproteins bypass SOCS inhibitory regulation remains poorly defined. Here, we demonstrate that co-expression of Bcr-Abl with SOCS-1 or SOCS-3 results in tyrosine phosphorylation of these SOCS proteins. Interestingly, SOCS-1 is highly tyrosine phosphorylated in one of five primary CML samples. Bcr-Abl-dependent tyrosine phosphorylation of SOCS-1 and SOCS-3 occurs mainly on Tyr 155 and Tyr 204 residues of SOCS-1, and Tyr 221 residue of SOCS-3. We observed that phosphorylation of these SOCS proteins was associated with their binding to Bcr-Abl. Bcr-Abl-dependent phosphorylation of SOCS-1 and SOCS-3 diminished their inhibitory effects on the activation of JAK and STAT5 and thereby enhanced JAK/STAT5 signaling. Strikingly, disrupting the tyrosine phosphorylation of SOCS-1 or SOCS-3 impaired the expression of Bcl-XL protein and sensitized K562 leukemic cells to undergo apoptosis. Moreover, selective mutation of tyrosine phosphorylation sites of SOCS-1 or SOCS-3 significantly blocked Bcr-Abl-mediated tumorigenesis in nude mice and inhibited Bcr-Abl-mediated murine bone marrow transformation. Together, these results reveal a mechanism of how Bcr-Abl may overcome SOCS-1 and SOCS-3 inhibition to constitutively activate the JAK/STAT-dependent signaling, and suggest that Bcr-Abl may critically requires tyrosine phosphorylation of SOCS-1 and SOCS-3 to mediate tumorigenesis when these SOCS proteins are present in cells.