Hoxworth Blood Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
Nat Commun. 2022 Jun 1;13(1):3056. doi: 10.1038/s41467-022-30651-7.
Acute B-cell lymphoblastic leukemia (B-ALL) results from oligo-clonal evolution of B-cell progenitors endowed with initiating and propagating leukemia properties. The activation of both the Rac guanine nucleotide exchange factor (Rac GEF) Vav3 and Rac GTPases is required for leukemogenesis mediated by the oncogenic fusion protein BCR-ABL. Vav3 expression becomes predominantly nuclear upon expression of BCR-ABL signature. In the nucleus, Vav3 interacts with BCR-ABL, Rac, and the polycomb repression complex (PRC) proteins Bmi1, Ring1b and Ezh2. The GEF activity of Vav3 is required for the proliferation, Bmi1-dependent B-cell progenitor self-renewal, nuclear Rac activation, protein interaction with Bmi1, mono-ubiquitination of H2A(K119) (H2AK119Ub) and repression of PRC-1 (PRC1) downstream target loci, of leukemic B-cell progenitors. Vav3 deficiency results in de-repression of negative regulators of cell proliferation and repression of oncogenic transcriptional factors. Mechanistically, we show that Vav3 prevents the Phlpp2-sensitive and Akt (S473)-dependent phosphorylation of Bmi1 on the regulatory residue S314 that, in turn, promotes the transcriptional factor reprogramming of leukemic B-cell progenitors. These results highlight the importance of non-canonical nuclear Rho GTPase signaling in leukemogenesis.
急性 B 淋巴细胞白血病（B-ALL）是由具有起始和增殖白血病特性的 B 细胞前体细胞的寡克隆进化引起的。致癌融合蛋白 BCR-ABL 介导的白血病发生需要 Rac 鸟嘌呤核苷酸交换因子（Rac GEF）Vav3 和 Rac GTPases 的激活。BCR-ABL 特征表达后，Vav3 表达主要在核内。在核内，Vav3 与 BCR-ABL、Rac 和多梳抑制复合物（PRC）蛋白 Bmi1、Ring1b 和 Ezh2 相互作用。Vav3 的 GEF 活性对于增殖、Bmi1 依赖性 B 细胞前体自我更新、核 Rac 激活、与 Bmi1 的蛋白相互作用、H2A（K119）的单泛素化（H2AK119Ub）和 PRC-1（PRC1）下游靶标基因的抑制是必需的。白血病 B 细胞前体。Vav3 缺陷导致细胞增殖的负调控因子去抑制和致癌转录因子的抑制。从机制上讲，我们表明 Vav3 可防止 Phlpp2 敏感和 Akt（S473）依赖性 Bmi1 在调节残基 S314 上的磷酸化，进而促进白血病 B 细胞前体的转录因子重编程。这些结果强调了非典型核 Rho GTPase 信号在白血病发生中的重要性。
