Synthetic Analysis on the mechanisms of survival and differentiation of hematopoietic cells

造血细胞存活和分化机制的综合分析

• 批准号: 18209034
• 负责人: KANAKURA Yuzuru
• 金额: $ 28.87万
• 依托单位: Osaka University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-18209034/
• 关键词: tyrosine kinase; apootosis; hematopoietic stem cell

1. Although leukemogenic tyrosine kinases activate common downstream molecules, the phenotypes of leukemia caused by these LTKs are distinct. In this study, we analyzed its mechanism using F1P1L1-PDGFRα(F-PRα), a causative gene of hypereosinophilic syndrome/chronic eosinophilic leukemia. When introduced into c-Kit^<high>Sca-1^+ Lineage cells (KSLs), F- PRa but not TEL-PDGFRβ (T-PRβ) enhanced the development of Gr-1^<+>IL-5Rα^<+> eosinophil progenitors(EoPs). Also, F- PRα promoted eosinophil development from common myeloid progenitors (CMPs). Furthermore, when expressed in megakaryocyte/erythrocyte progenitors (MEPs) and common lymphoid progenitors (CLPs), F-PRα aberrantly developed EoPs from MEPs and CLPs. Regarding this mechanism, RT-PCR analysis revealed that F-PRα augmented the expression of C/EBPα and GATA-2, while it reduced PU. 1 expression. Furthermore, F-PRα and its downstream Ras enhanced GATA- 2 activity, while they inhibited PU.1 activity in luciferase assays.2. We previously cloned a novel anti-apoptotic gene, Anamorsin(AM). In this study, we generated transgenic(Tg) mice for AM. Although AM Tg mice did not develop any tumors spontaneously, marked splenomegaly due to the outgrowth of B cells was observed. In addition, we found that the expression of AM was a poor prognostic factor for the special subtype of diffuse large B-cell lymphoma using immunohistochemical staining.3. We developed a long-term culture system to produce B lymphocytes from human CD34_+ cells purified from umbilical cord blood using human mesenchymal stem cells (hMSC) as stroma. Using this cocultures, we could develop 1-5 x 10^<5> CD10_+ cells from 2000 CD34_+ cells. In this system, surface IgM_+ immature B cells began to appear after 4 weeks. In addition, we found that Activin A selectively suppressed B lymphocyte production.

1.尽管致白血病酪氨酸激酶激活了常见的下游分子，但这些LTK引起的白血病的表型是不同的。在本研究中，我们利用高嗜酸性粒细胞综合征/慢性嗜酸性粒细胞白血病的致病基因F1P1L1-PDGFRα(F-PRα)来分析其机制。将F-PRβ(T-PRβ)导入c-Kit^&gt；High&gt；Sca-1^+系细胞(KSL)后，可促进Gr-1^&lt；+&gt；IL-5Rα^&gt；+&gt；嗜酸性粒细胞前体(EOPs)的发育。此外，F-PRα还促进了普通髓系祖细胞(CMPS)的嗜酸性粒细胞发育。此外，当F-PRα在巨核/红系祖细胞(MEP)和普通淋巴祖细胞(CLP)中表达时，它们会从MEP和CLP异常地发展成EOP。对于这一机制，逆转录聚合酶链式反应分析表明，F-PRα上调了C/EBpα和GATA-2的表达，而降低了PU。1个表达式。此外，在荧光素酶分析中，F-PRα及其下游RAS增强GATA-2活性，而抑制PU1活性。我们先前克隆了一个新的抗细胞凋亡基因Anamorsin(AM)。在这项研究中，我们产生了AM的转基因(TG)小鼠虽然AM-TG小鼠没有自发形成任何肿瘤，但由于B细胞的生长，观察到明显的脾肿大。另外，免疫组织化学染色发现AM的表达是弥漫性大B细胞淋巴瘤这一特殊亚型的不良预后因素。以人骨髓间充质干细胞(HMSC)为基质，建立了从脐带血中分离纯化的CD34+细胞制备B淋巴细胞的长期培养体系。利用此共培养体系，可从2000个CD34~+细胞中培养出1~5×10~(-5)×10~(-5)~(-1)CD10~+细胞。在该系统中，4周后开始出现表面IgM+的未成熟B细胞。此外，我们发现激活素A选择性地抑制B淋巴细胞的产生。

项目成果

Identification of amino‐terminal region of adiponectin as a physiologically functional domain

• DOI: 10.1002/jcb.20779
• 发表时间: 2006-05
• 期刊: Journal of Cellular Biochemistry
• 影响因子: 4
• 作者: H. Ujiie;K. Oritani;H. Kato;T. Yokota;Isao Takahashi;T. Maeda;H. Masaie;M. Ichii;Y. Kamada;S. Tamura;S. Kihara;T. Funahashi;Y. Tomiyama;Y. Kanakura

STAP-2 regulates c-Fms/M-CSF receptor signaling in murine macrophage Raw 264.7 cells

• DOI: 10.1016/j.bbrc.2007.05.030
• 发表时间: 2007-07-06
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Ikeda, Osamu;Sekine, Yuichi;Matsuda, Tadashi
• 通讯作者: Matsuda, Tadashi

FIP1L1/PDGFRα imposes commitment towards eosinophil lineage on hematopoietic stem/progenitor cells by modifying the expression and function of lineage specific transcription factors.

FIP1L1/PDGFRα 通过改变谱系特异性转录因子的表达和功能，对造血干细胞/祖细胞施加对嗜酸性粒细胞谱系的承诺。

• 发表时间: 2007
• 作者: Fukushima K;et. al.
• 通讯作者: et. al.

SFRPl is estrogen inducible in bone marrow stromal cells and suppresses the earliest events in lymphopoiesis.

SFRP1是骨髓基质细胞中可诱导的雌激素并且抑制淋巴细胞生成的最早事件。

• 发表时间: 2007
• 作者: Nagaoka T;Katayama Y;Kano T;Kobayashi K.;Oshima H;Fukaya C;Yamamoto T;Yokota T,.
• 通讯作者: Yokota T,.

Regulation by the TGF R superfamily of human B lymphopoiesis by in a newly established lymphocyt e culture system using human mesenchymal stem cells as a s nnnnrtive miernenvirnnment

使用人间充质干细胞作为新建立的淋巴细胞培养系统，TGF R 超家族对人 B 淋巴细胞生成的调节

• 发表时间: 2007
• 作者: Ichii;M;et. al.
• 通讯作者: et. al.