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Mechanisms in hematopoiesis and leukemogenesis by the transcription factor TEL

转录因子 TEL 的造血和白血病发生机制

基本信息

批准号：
14370308
负责人：
MITANI Kinuko
金额：
$ 7.81万
依托单位：
Dokkyo Medical University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

Regulation in hematopoiesis by TEL.(1)We demonstrated that TEL stimulates the erythroid differentiation induced by chemical compounds hemin and DMSO in murine erythroleukemia MEL cells. To confirm this TEL's effect in a more physiological setting, we introduced TEL cDNA into human leukemia UT7/GM cells. TEL accelerated the erythroid differentiation induced by erythropoietin and inhibited the megakaryocytic differentiation induced by thrombopoietin. These data suggest that TEL could decide the cell fate in differentiation in erythroid/megakaryocytic common progenitor.(2)We also examined regulatory mechanisms in the TEL's function. TEL was found to be phosphorylated by the MAP kinase ERK. Hyperphosphorylated TEL lost its transcription repressive ability and tumor suppressive function, and exerted dominant-negative effect over hypophosphorylated TEL. On the other hand, various types of isoform were observed expressed from the TEL gene. Among them, ΔHLH and ΔETS isoforms were dominant-inhibitory molecules for wild-type TEL. We showed that expression frequency of ΔETS isoform was increased in myelodysplastic syndrome-derived leukemia in comparison to myelodysplastic syndrome in early phase.Mechanism in leukemogenesis by TEL.(1)TEL/AML1 generated by t(12;21) in childhood pre-B cell acute lymphoblastic leukemia is known to dominantly repress wild-type AML1's function. We showed that TEL/AML1 also inhibits wild-type TEL's function. Loss of tumor suppressive function from TEL could pay a causative role in leukemogenesis by t(12;21).(2)We cloned a novel TEL/PTPRR chimeric gene generated by inv(12) in acute myelogenous leukemia. TEL/PTPRR had dominant-negative function over wild-type TEL in molecular assays. Furthermore, UT7/GM cells overexpressing TEL/PTPRR acquired factor-independent growth, and maintained high level of phosphorylation in STAT3 even after factor withdrawal. We conclude that TEL/PTPRR causes leukemia through inactivating TEL and stimulating STAT3 signal.

TEL对造血的调节作用。(1)我们证实了TEL能刺激化合物氯化高铁血红素和二甲基亚砜诱导小鼠红白血病细胞向红系分化。为了在更具生理学意义的环境中证实TEL的作用，我们将TEL基因导入人白血病UT7/GM细胞。TEL促进促红细胞生成素诱导的红系分化，抑制促血小板生成素诱导的巨核细胞分化。这些数据表明TELs可能决定了红系/巨核系共同祖细胞分化过程中的细胞命运。(2)我们还研究了TELs功能的调控机制。TEL被发现被MAP激酶ERK磷酸化。过度磷酸化的TEL失去了转录抑制能力和肿瘤抑制功能，对低磷酸化的TEL产生显性-负性效应。另一方面，从TEL基因中观察到不同类型的异构体表达。其中，ΔH1H和ΔEts亚型是野生型TEL的显性抑制分子。我们发现ΔEts亚型在早期骨髓增生异常综合征衍生的白血病中的表达频率比骨髓增生异常综合征高。(1)t(12；21)在儿童前B细胞急性淋巴细胞白血病中产生的TEL/AML1已知主要抑制野生型AML1‘S功能。我们发现TEL/AML1也抑制野生型TEL的功能。TEL抑制肿瘤功能的丧失可能通过t(12；21)在白血病的发生中起作用。(2)我们克隆了一个由inv(12)在急性髓系白血病中产生的新的TEL/PTPRR嵌合基因。在分子检测中，TEL/PTPRR对野生型TEL具有显性-负性作用。此外，过表达TEL/PTPRR的UT7/GM细胞获得了不依赖于因子的生长，并且即使在因子退出后也保持了STAT3的高水平磷酸化。我们认为TEL/PTPRR通过失活TEL和刺激STAT3信号导致白血病的发生。