小柯机器人

美国辛辛那提大学Daniel T. Starczynowski、纽约大学Iannis Aifantis等研究人员合作发现，TRAF6通过直接靶向MYC致癌活性在髓系恶性肿瘤中发挥肿瘤抑制作用。相关论文于2022年1月18日在线发表在《细胞—干细胞》杂志上。

为了识别与前白血病细胞合作的信号状态，研究人员使用了体内 RNAi 筛选方法。鉴定出的最突出基因之一是泛素连接酶TRAF6。白血病前期细胞中TRAF6的缺失导致明显的髓性白血病，并与MYC依赖性干细胞特征相关。TRAF6在一部分髓系恶性肿瘤患者中受到抑制，这表明TRAF6信号传导的破坏可导致急性白血病。从机制上讲，TRAF6泛素化MYC，这一事件不会影响其蛋白质稳定性，而是通过拮抗乙酰化修饰来抑制其功能活性。

据介绍，克隆性造血（CH）是一种与衰老相关的疾病，其特征在于获得特定突变前白血病细胞的克隆生长。尽管患有CH的人是健康的，但他们患髓系恶性肿瘤的风险增加，这表明从白血病前期阶段过渡到明确的白血病阶段需要额外的改变。

附：英文原文

Title: TRAF6 functions as a tumor suppressor in myeloid malignancies by directly targeting MYC oncogenic activity

Author: Tomoya Muto, Maria Guillamot, Jennifer Yeung, Jing Fang, Joshua Bennett, Bettina Nadorp, Audrey Lasry, Luna Zea Redondo, Kwangmin Choi, Yixiao Gong, Callum S. Walker, Kathleen Hueneman, Lyndsey C. Bolanos, Laura Barreyro, Lynn H. Lee, Kenneth D. Greis, Nikita Vasyliev, Alireza Khodadadi-Jamayran, Evgeny Nudler, Amaia Lujambio, Scott W. Lowe, Iannis Aifantis, Daniel T. Starczynowski

Issue&Volume: 2022-01-18

Abstract: Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonaloutgrowth of pre-leukemic cells that acquire specific mutations. Although individualswith CH are healthy, they are at an increased risk of developing myeloid malignancies,suggesting that additional alterations are needed for the transition from a pre-leukemiastage to frank leukemia. To identify signaling states that cooperate with pre-leukemiccells, we used an in vivo RNAi screening approach. One of the most prominent genes identified was the ubiquitinligase TRAF6. Loss of TRAF6 in pre-leukemic cells results in overt myeloid leukemiaand is associated with MYC-dependent stem cell signatures. TRAF6 is repressed in asubset of patients with myeloid malignancies, suggesting that subversion of TRAF6signaling can lead to acute leukemia. Mechanistically, TRAF6 ubiquitinates MYC, anevent that does not affect its protein stability but rather represses its functionalactivity by antagonizing an acetylation modification.

DOI: 10.1016/j.stem.2021.12.007

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00491-4

Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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