文章：

TNFAIP3的缺失增强了MYD88L265P驱动的非霍奇金淋巴瘤信号传导

Loss of TNFAIP3 enhances MYD88L265P-driven signaling in non-Hodgkin lymphoma

原文发布日期：2018-10-09

DOI: 10.1038/s41408-018-0130-3

类型: Article

开放获取: 是

英文摘要：

MYD88 mutations are one of the most recurrent mutations in hematologic malignancies. However, recent mouse models suggest that MYD88L265P alone may not be sufficient to induce tumor formation. Interplay between MYD88L265P and other genetic events is further supported by the fact that TNFAIP3 (A20) inactivation often accompanies MYD88L265P. However, we are still lacking information about the consequence of MYD88L265P in combination with TNFAIP3 loss in human B cell lymphoma. Review of our genetic data on diffuse large B cell lymphoma (DLBCL) and Waldenstrom macroglobulinemia (WM), found that a large percentage of DLBCL and WM cases that have a MYD88 mutation also harbor a TNFAIP3 loss, 55% DLBCL and 28% of WM, respectively. To mimic this combination of genetic events, we used genomic editing technology to knock out TNFAIP3 in MYD88L265P non-Hodgkin’s lymphoma (NHL) cell lines. Loss of A20 expression resulted in increased NF-κB and p38 activity leading to upregulation of the NF-κB target genes BCL2 and MYC. Furthermore, we detected the increased production of IL-6 and CXCL10 which led to an upregulation of the JAK/STAT pathway. Overall, these results suggest that MYD88L265P signaling can be enhanced by a second genetic alteration in TNFAIP3 and highlights a potential opportunity for therapeutic targeting.

摘要翻译： 

MYD88突变是血液恶性肿瘤中最常见的突变之一。然而，近期小鼠模型研究表明，仅MYD88L265P可能不足以诱导肿瘤形成。MYD88L265P与其他遗传事件之间存在相互作用，这一观点进一步得到了TNFAIP3（A20）失活常伴随MYD88L265P发生这一事实的支持。但关于MYD88L265P与TNFAIP3缺失在人B细胞淋巴瘤中共同作用的后果，我们仍缺乏相关信息。通过回顾我们关于弥漫大B细胞淋巴瘤（DLBCL）和华氏巨球蛋白血症（WM）的遗传学数据，发现携带MYD88突变的DLBCL和WM病例中有很大比例同时存在TNFAIP3缺失，分别为55%的DLBCL和28%的WM。为模拟这种遗传事件组合，我们采用基因组编辑技术在MYD88L265P非霍奇金淋巴瘤（NHL）细胞系中敲除TNFAIP3。A20表达的缺失导致NF-κB和p38活性增强，进而引起NF-κB靶基因BCL2和MYC的上调。此外，我们检测到IL-6和CXCL10的产量增加，这导致了JAK/STAT通路的上调。总体而言，这些结果表明MYD88L265P信号传导可通过TNFAIP3的二次遗传改变而增强，并揭示了潜在的治疗靶向机遇。

原文链接：

Loss of TNFAIP3 enhances MYD88L265P-driven signaling in non-Hodgkin lymphoma