文章：

外周T细胞淋巴瘤中磷酸化STAT3与蛋白酪氨酸磷酸酶-6的预后及治疗意义

Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma

原文发布日期：2018-11-12

DOI: 10.1038/s41408-018-0138-8

类型: Article

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英文摘要：

Peripheral T cell lymphomas (PTCL) is a heterogenous group of non-Hodgkin lymphoma and many patients remain refractory to the frontline therapy. Identifying new prognostic markers and treatment is an unmet need in PTCL. We analyzed phospho-STAT3 (pSTAT3) expression in a cohort of 169 PTCL tumors and show overall 38% positivity with varied distribution among PTCL subtypes with 27% (16/59) in PTCL-NOS; 29% (11/38) in AITL, 57% (13/28) in ALK-negative ALCL, and 93% in ALK-pos ALCL (14/15), respectively. Correlative analysis indicated an adverse correlation between pSTAT3 and overall survival (OS). PTPN6, a tyrosine phosphatase and potential negative regulator of STAT3 activity, was suppressed in 62% of PTCL-NOS, 42% of AITL, 60% ALK-neg ALCL, and 86% of ALK-pos ALCL. Loss of PTPN6 combined with pSTAT3 positivity predicted an infwere considered significantferior OS in PTCL cases. In vitro treatment of TCL lines with azacytidine (aza), a DNA methyltransferase inhibitor (DNMTi), restored PTPN6 expression and decreased pSTAT3. Combining DNMTi with JAK3 inhibitor resulted in synergistic antitumor activity in SUDHL1 cell line. Overall, our results suggest that PTPN6 and activated STAT3 can be developed as prognostic markers, and the combination of DNMTi and JAK3 inhibitors as a novel treatment for patients with PTCL subtypes.

摘要翻译： 

外周T细胞淋巴瘤（PTCL）是一组异质性的非霍奇金淋巴瘤，许多患者对一线治疗仍难以奏效。识别新的预后标志物和治疗方法是目前PTCL领域亟待解决的问题。我们分析了169例PTCL肿瘤中磷酸化STAT3（pSTAT3）的表达情况，结果显示总体阳性率为38%，但在不同PTCL亚型中分布不均：PTCL-NOS为27%（16/59）、AITL为29%（11/38）、ALK阴性ALCL为57%（13/28）、ALK阳性ALCL为93%（14/15）。相关性分析表明pSTAT3与总生存期（OS）呈负相关。酪氨酸磷酸酶PTPN6作为STAT3活性的潜在负调控因子，其在各亚型中的抑制率分别为PTCL-NOS 62%、AITL 42%、ALK阴性ALCL 60%、ALK阳性ALCL 86%。PTPN6缺失合并pSTAT3阳性的PTCL病例预后更差。通过DNA甲基转移酶抑制剂阿扎胞苷进行体外处理，可恢复T细胞淋巴瘤细胞系中PTPN6表达并降低pSTAT3水平。在SUDHL1细胞系中，DNA甲基转移酶抑制剂与JAK3抑制剂联用显示出协同抗肿瘤活性。本研究提示PTPN6和活化STAT3可作为PTCL亚型的预后标志物，而DNA甲基转移酶抑制剂与JAK3抑制剂的联合疗法有望成为新型治疗策略。

原文链接：

Prognostic and therapeutic significance of phosphorylated STAT3 and protein tyrosine phosphatase-6 in peripheral-T cell lymphoma