Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Department of Pathology and Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA.
Cell Stem Cell. 2022 Feb 3;29(2):298-314.e9. doi: 10.1016/j.stem.2021.12.007. Epub 2022 Jan 18.
Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of pre-leukemic cells that acquire specific mutations. Although individuals with 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-leukemia stage to frank leukemia. To identify signaling states that cooperate with pre-leukemic cells, we used an in vivo RNAi screening approach. One of the most prominent genes identified was the ubiquitin ligase TRAF6. Loss of TRAF6 in pre-leukemic cells results in overt myeloid leukemia and is associated with MYC-dependent stem cell signatures. TRAF6 is repressed in a subset of patients with myeloid malignancies, suggesting that subversion of TRAF6 signaling can lead to acute leukemia. Mechanistically, TRAF6 ubiquitinates MYC, an event that does not affect its protein stability but rather represses its functional activity by antagonizing an acetylation modification.
克隆性造血 (CH) 是一种与衰老相关的疾病，其特征是白血病前细胞获得特定突变的克隆性生长。虽然 CH 患者健康状况良好，但他们患骨髓恶性肿瘤的风险增加，这表明从白血病前期到白血病的过渡需要额外的改变。为了确定与白血病前细胞合作的信号状态，我们使用了体内 RNAi 筛选方法。鉴定出的最突出的基因之一是泛素连接酶 TRAF6。白血病前细胞中 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 在一部分骨髓恶性肿瘤患者中受到抑制，提示 TRAF6 信号的颠覆可能导致急性白血病。在机制上，TRAF6 泛素化 MYC，该事件不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。
