文章：

MYD88 L265P激活TAK1驱动非霍奇金淋巴瘤恶性B细胞生长

Activation of TAK1 by MYD88 L265P drives malignant B-cell Growth in non-Hodgkin lymphoma

原文发布日期：2014-02-14

DOI: 10.1038/bcj.2014.4

类型: Original Article

开放获取: 是

英文摘要：

Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHLs) including the rare lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia (WM). Using whole-exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B-cell survival, therapeutic targeting of MYD88 signaling pathways may be clinically useful. However, we are lacking a thorough characterization of the role of intermediary signaling proteins on the biology of MYD88L265P-expressing B cells. We report here that MYD88L265P signaling is constitutively active in both WM and diffuse large B-cell lymphoma cells leading to heightened MYD88L265P, IRAK and TRAF6 oligomerization and NF-κB activation. Furthermore, we have identified the signaling protein, TAK1, to be an essential mediator of MYD88L265P-driven signaling, cellular proliferation and cytokine secretion in malignant B cells. Our studies highlight the biological significance of MYD88L265P in NHL and reveal TAK1 inhibition to be a potential therapeutic strategy for the treatment of WM and other diseases characterized by MYD88L265P.

摘要翻译： 

大规模并行测序分析显示，MYD88基因常见突变（MYD88L265P）在包括罕见淋巴浆细胞淋巴瘤——华氏巨球蛋白血症在内的多种非霍奇金淋巴瘤中高频出现。通过全外显子组测序、桑格测序和等位基因特异性PCR技术，我们验证了前期研究结果，在97%的华氏巨球蛋白血症患者（样本量=39）肿瘤基因组中检测到MYD88L265P突变。鉴于MYD88突变在华氏巨球蛋白血症及其他非霍奇金淋巴瘤中的高发性及其对恶性B细胞存活的已知影响，针对MYD88信号通路的治疗干预可能具有临床价值。然而，目前对中间信号蛋白在表达MYD88L265P的B细胞生物学中的作用尚缺乏系统表征。本研究发现MYD88L265P信号在华氏巨球蛋白血症和弥漫性大B细胞淋巴瘤细胞中持续激活，导致MYD88L265P、IRAK和TRAF6寡聚化增强及NF-κB活化。更重要的是，我们发现信号蛋白TAK1是恶性B细胞中MYD88L265P驱动信号传导、细胞增殖和细胞因子分泌的关键介质。本研究揭示了MYD88L265P在非霍奇金淋巴瘤中的生物学重要性，并证明TAK1抑制可能成为治疗华氏巨球蛋白血症及其他MYD88L265P相关疾病的潜在治疗策略。

原文链接：

Activation of TAK1 by MYD88 L265P drives malignant B-cell Growth in non-Hodgkin lymphoma