Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis.
Nuclear Vav3 is required for polycomb repression complex-1 activity in B-cell lymphoblastic leukemogenesis.
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B 细胞淋巴母细胞白血病发生中，核 Vav3 是多梳抑制复合物 1 活性所必需的。
DOI：
10.1038/s41467-022-30651-7
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发表时间：
2022-06-01
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
急性B淋巴细胞白血病（B-ALL）是由具有引发和增殖白血病特性的B细胞祖细胞的寡克隆进化引起的。由致癌融合蛋白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）Vav 3和Rac GTP酶的激活。在细胞核中，Vav 3与BCR-ABL、Rac和多梳阻遏复合物（PRC）蛋白Bmi 1、Ring 1b和Ezh 2相互作用。Vav 3的GEF活性对于白血病B细胞祖细胞的增殖、Bmi 1依赖性B细胞祖细胞自我更新、核Rac活化、与Bmi 1的蛋白质相互作用、H2 A（K119）（H2 AK 119 Ub）的单泛素化和PRC-1（PRC 1）下游靶基因座的抑制是必需的。Vav 3缺陷导致细胞增殖的负调节因子的去抑制和致癌转录因子的抑制。从机制上讲，我们表明Vav 3可以阻止Bmi 1在调节残基S314上的Phlpp 2敏感性和Akt（S473）依赖性磷酸化，从而促进白血病B细胞祖细胞的转录因子重编程。这些结果突出了非经典核Rho GTdR信号转导在白血病发生中的重要性。Ph+和Ph样B-ALL仍是预后不良的白血病。VAV 3是一种鸟嘌呤核苷酸交换因子，在这些白血病中被激活并过表达。在这里，作者揭示了白血病VAV 3主要是核的。核VAV 3通过其鸟嘌呤核苷酸交换因子及其效应核RAC 2，通过核AKT/PHLPP 2调节的BMI 1控制多梳阻遏复合物-1的阻遏转录活性。
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. Ph+ and Ph-like B-ALL remain poor prognosis leukemias. VAV3, a guanine nucleotide exchange factor, is activated and overexpressed in these leukemias. Here the authors reveal that leukemic VAV3 is predominantly nuclear. Nuclear VAV3, through its guanine nucleotide exchange factor and its effector nuclear RAC2, controls the repressive transcriptional activity of the polycomb repression complex-1 via nuclear AKT/PHLPP2 regulated BMI1.
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影响因子：
15.3
作者：
Fujikawa, K;Miletic, AV;Alt, FW;Faccio, R;Brown, T;Hoog, J;Fredericks, J;Nishi, S;Mildiner, S;Moores, SL;Brugge, J;Rosen, FS;Swat, W
通讯作者：
Swat, W
影响因子：
82.9
作者：
Castor, A;Nilsson, L;Jacobsen, SEW
通讯作者：
Jacobsen, SEW
影响因子：
158.5
作者：
Aricò, M;Valsecchi, MG;Masera, G
通讯作者：
Masera, G
影响因子：
14.9
作者：
Chen J;Bardes EE;Aronow BJ;Jegga AG
通讯作者：
Jegga AG
影响因子：
16
作者：
Brognard, John;Sierecki, Emma;Newton, Alexandra C.
通讯作者：
Newton, Alexandra C.