Loss of TNFAIP3 enhances MYD88L265P-driven signaling in non-Hodgkin lymphoma.,Blood Cancer Journal

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Loss of TNFAIP3 enhances MYD88L265P-driven signaling in non-Hodgkin lymphoma.
Blood Cancer Journal ( IF 12.9 ) Pub Date : 2018-Oct-09 , DOI: 10.1038/s41408-018-0130-3
Kerstin Wenzl ₁ , Michelle K Manske ₁ , Vivekananda Sarangi ₂ , Yan W Asmann ₃ , Patricia T Greipp ₄ , Hanna R Schoon ₁ , Esteban Braggio ₅ , Matthew J Maurer ₂ , Andrew L Feldman ₆ , Thomas E Witzig ₁ , Susan L Slager ₂ , Stephen M Ansell ₁ , James R Cerhan ₂ , Anne J Novak ₁

Affiliation

MYD88 mutations are one of the most recurrent mutations in hematologic malignancies. However, recent mouse models suggest that MYD88_L265P alone may not be sufficient to induce tumor formation. Interplay between MYD88_L265P and other genetic events is further supported by the fact that TNFAIP3 (A20) inactivation often accompanies MYD88_L265P. However, we are still lacking information about the consequence of MYD88_L265P 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 MYD88_L265P 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 MYD88_L265P signaling can be enhanced by a second genetic alteration in TNFAIP3 and highlights a potential opportunity for therapeutic targeting.

中文翻译：

TNFAIP3 的缺失增强了非霍奇金淋巴瘤中 MYD88L265P 驱动的信号传导。

MYD88 突变是血液系统恶性肿瘤中最常见的突变之一。然而，最近的小鼠模型表明，单独的 MYD88 _L265P可能不足以诱导肿瘤形成。_{TNFAIP3 (A20) 失活经常伴随 MYD88 L265P}的事实进一步支持了 MYD88 _L265P与其他遗传事件之间的相互作用。_{然而，我们仍然缺乏有关 MYD88 L265P}与 TNFAIP3 缺失联合治疗人 B 细胞淋巴瘤的后果的信息。回顾我们关于弥漫性大 B 细胞淋巴瘤 (DLBCL) 和华氏巨球蛋白血症 (WM) 的遗传数据，发现大部分具有 MYD88 突变的 DLBCL 和 WM 病例也存在 TNFAIP3 缺失，其中 55% 的 DLBCL 和 28% 的 WM 存在 TNFAIP3 缺失。，分别。为了模拟这种遗传事件的组合，我们使用基因组编辑技术敲除 MYD88 _L265P非霍奇金淋巴瘤 (NHL) 细胞系中的 TNFAIP3。A20 表达缺失导致 NF-κB 和 p38 活性增加，从而导致 NF-κB 靶基因 BCL2 和 MYC 上调。此外，我们检测到 IL-6 和 CXCL10 产量增加，导致 JAK/STAT 通路上调。总体而言，这些结果表明TNFAIP3 的第二次基因改变可以增强MYD88 _{L265P信号传导，并强调了治疗靶向的潜在机会。}

更新日期：2019-01-26

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