Comprehensive analysis of oncogenic transcriptional factor Evi-1.

致癌转录因子Evi-1的综合分析。

• 批准号: 17390273
• 负责人: KUROKAWA Mineo
• 金额: $ 8.83万
• 依托单位: The University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390273/
• 关键词: Evi-1; leukemia; isoform; oligomerization; knockout mice; hematopoietic stem cell; 多量体; 造腫瘍性; TGF-β; CtBP; AML1-Evi-1; AP-1

Evi-1 is a member of the SET/PR domain family of transcription factors whose inappropriate expression leads to leukemic transformation. Two distinct alternative forms, Evi-1a and Evi-1c, are generated from the Evi-1 gene. Although Evi-1a (PR-absent form) is widely recognized as an oncoprotein, a role for Evi-1c (PR-containing form) in leukemogenesis has not been elucidated. In this study, we showed that Evi-la forms homo-oligomers while Evi-1c exclusively exists as a monomer. Remarkably, Evi-1c has lost the ability to interact with CtBP, and to repress TGF-β signaling. These results indicate that oligomeraization contributes to the oncogenic potential of Evi-1.Next, We created Evi-1 mutant mice to investigate the in vivo role of Evi-1 in hematopoiesis and leukemogenesis. Using these mice, we showed that Evi-1 regulates proliferative capacity of hematopoietic stem cells in a dose-dependent manner both during embryogenesis and in adults. In contrast, Evi-1 is dispensable for blood cell lineage commitment. We further demonstrated that disruption of Evi-1 in leukemic cells transformed by MLL/ENL or E2A/HLF leads to significant loss of their proliferative activity. These results suggest that Evi-1 is a critical regulator for the proliferation of normal and leukemic cells.

Evi-1 是转录因子 SET/PR 结构域家族的成员，其不适当的表达会导致白血病转化，Evi-1a 和 Evi-1c 是由 Evi-1 基因产生的。 （PR 缺失形式）被广泛认为是一种癌蛋白，但 Evi-1c（含 PR 形式）在白血病发生中的作用尚未阐明。 Evi-la 形成同源寡聚体，而 Evi-1c 仅作为单体存在。值得注意的是，Evi-1c 失去了与 CtBP 相互作用和抑制 TGF-β 信号传导的能力。这些结果表明寡聚化有助于增强其致癌潜力。 Evi-1. 接下来，我们创建了 Evi-1 突变小鼠来研究 Evi-1 在造血和白血病发生中的体内作用，我们证明了这一点。 Evi-1 在胚胎发生期间和成体中以剂量依赖性方式调节造血干细胞的增殖能力，相反，Evi-1 对于转化的白血病细胞中的血细胞谱系定型而言是可有可无的。 MLL/ENL 或 E2A/HLF 导致其增殖活性显着丧失。这些结果表明 Evi-1 是正常细胞和白血病细胞增殖的关键调节因子。

项目成果

Durable remission after the administration of rituximab for EBV-negative diffuse large B-cell lymphoma arising after autologous peripheral blood stem cell transplantation for angioimmunoblastic T-cell lymphoma.

治疗血管免疫母细胞 T 细胞淋巴瘤的自体外周血干细胞移植后出现的 EBV 阴性弥漫性大 B 细胞淋巴瘤，使用利妥昔单抗后可获得持久缓解。

• 发表时间: 2007
• 作者: Shinohara A; Asai T; Izutsu K; Ota Y; Takeuchi K; Hangaishi A; Kanada Y; Chiba S; Motokura T; Kurokawa M.
• 通讯作者: Kurokawa M.

Oligomerization of Evi-1 regulated by the PR domain contributes to recruitment of corepressor CtBP.

PR 结构域调节的 Evi-1 寡聚化有助于辅阻遏物 CtBP 的募集。

• 发表时间: 2005
• 作者: Nitta E; Izutsu K; Yamaguchi Y; Imai Y; Ogawa S; Chiba S; Kurokawa M; Hirai H.
• 通讯作者: Hirai H.

A high incidence of late-onset neutropenia following rituximab-containing chemotherapy as a primary treatment of CD20-positive β-cell lymphoma : a single-institution study.

含有利妥昔单抗的化疗作为 CD20 阳性 β 细胞淋巴瘤的主要治疗方法后迟发性中性粒细胞减少症的发生率很高：一项单机构研究。

• 发表时间: 2007
• 作者: Nitta E; Izutsu K; Sato T; Ota Y; Takeuchi K; Kamijo A; Takahashi K; Oshima K; K;a Y; Chiba S; Motokura T; Kurokawa M.
• 通讯作者: Kurokawa M.

FDG-PET in T-cell and NK-cell neoplasms.

T 细胞和 NK 细胞肿瘤中的 FDG-PET。

• 作者: Kako S; Izutsu K; Ohta Y; Minatani Y; Sugaya M; Momose T; Ohtomo K; K;a Y; Chiba S; Motokura T; Kurokawa M
• 通讯作者: Kurokawa M

FDG-PET in T-cell and NK-cell neoplasms.

T 细胞和 NK 细胞肿瘤中的 FDG-PET。

• 作者: Kako S; Izutsu K; Ohta Y; Minatani Y; Sugaya M; Momose T; Ohtomo K; K;a Y; Chiba S; Motokura T; Kurokawa M.
• 通讯作者: Kurokawa M.