Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation
Elevated serum IL-10 levels in diffuse large B-cell lymphoma: a mechanism of aberrant JAK2 activation
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DOI：
10.1182/blood-2011-10-388538
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发表时间：
2012-03-22
期刊：
影响因子：
20.3
通讯作者：
Witzig, Thomas E.
中科院分区：
文献类型：
--
作者：
Gupta, Mamta;Han, Jing Jing;Witzig, Thomas E.
细胞因子在癌症中失调，并可促进肿瘤生长。在弥漫性大细胞淋巴瘤（DLBCL）患者中，我们观察到与JAK/STAT通路相关的血清细胞因子（即IL-6、IL-10、表皮生长因子和IL-2）水平高于对照组。其中，只有IL-10在体外激活淋巴瘤细胞中的JAK 2通路。血清IL-10水平高的患者比血清IL-10水平低的患者的无事件生存期短（P> 0.01），高IL-10与高乳糖酶脱氢酶（P= 0.0085）和较高的国际预后指数评分（P= 0.01）相关。为了探索IL-10可能导致较差EFS的机制，我们研究了IL-10对JAK 2通路的影响，发现IL-10/IL-10受体复合物上调JAK 2信号传导。针对IL-10的中和Ab抑制组成型和IL-10诱导的JAK 2/STAT 3磷酸化。JAK 2抑制使JAK 2和STAT 3去磷酸化，并对磷酸化JAK 2阳性DLBCL细胞产生抑制作用;对磷酸化JAK 2阴性细胞的影响极小。JAK 2抑制诱导的细胞凋亡依赖于自分泌IL-10和c-myc表达的抑制，而不依赖于Bcl-2家族的表达。这些结果提供了在DLBCL患者中测试JAK 2抑制剂的基本原理，并表明血清IL-10可能是识别更可能对JAK 2靶向治疗有反应的患者的生物标志物。（血。2012; 119（12）：2844-2853）
Cytokines are deregulated in cancers and can contribute to tumor growth. In patients with diffuse large-cell lymphoma (DLBCL), we observed higher levels of JAK/STAT pathway-related serum cytokines (ie, IL-6, IL-10, epidermal growth factor, and IL-2) compared with controls. Of these, only IL-10 activated the JAK2 pathway in lymphoma cells in vitro. Patients with high serum IL-10 had shorter event-free survival (EFS) than patients with low levels (P>.01) and high IL-10 was correlated with high lactase dehydrogenase (P=.0085) and higher International Prognostic Index scores (P=.01). To explore the mechanism by which IL-10 may contribute to an inferior EFS, we investigated the effect of IL-10 on the JAK2 pathway and found that the IL-10/IL-10 receptor complex upregulated JAK2 signaling. Neutralizing Ab to IL-10 inhibited constitutive and IL-10-induced JAK2/STAT3 phosphorylation. JAK2 inhibition dephosphorylated JAK2 and STAT3 and caused an inhibitory effect on phospho-JAK2-positive DLBCL cells; there was a minimal effect on phospho-JAK2-negative cells. Apoptosis induced by JAK2 inhibition was dependent on inhibition of autocrine IL-10 and c-myc expression and independent of Bcl-2 family expression. These results provide the rationale for testing JAK2 inhibitors in DLBCL patients, and indicate that serum IL-10 may be a biomarker to identify patients more likely to respond to JAK2-targeted therapy. (Blood. 2012; 119(12): 2844-2853)