Mechanisms in hematopoiesis and leukemogenesis by the transcription factor TEL

通过TEL调节造血。(1)We证明TEL刺激由化合物氯化血红素和DMSO诱导的鼠红白血病MEL细胞中的红系分化。为了证实这种TEL在更生理环境中的作用，我们将TEL cDNA引入人白血病UT 7/GM细胞中。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系分化。这些数据表明，TEL可以决定细胞命运的分化在红系/巨核细胞共同祖细胞。(2)We还研究了TEL功能的调节机制。发现TEL被MAP激酶ERK磷酸化。过度磷酸化的TEL失去了其转录抑制能力和抑瘤功能，并对低磷酸化的TEL产生显性负效应。另一方面，观察到从TEL基因表达的各种类型的同种型。其中，ΔHLH和ΔETS是野生型TEL的显性抑制分子。我们发现，与早期骨髓增生异常综合征相比，骨髓增生异常综合征衍生的白血病中ΔETS亚型的表达频率增加。（1）已知儿童前B细胞急性淋巴细胞白血病中由t（12;21）产生的TEL/AML 1主要抑制野生型AML 1的功能。我们发现，TEL/AML 1也抑制野生型TEL的功能。TEL的肿瘤抑制功能丧失可能在t（12;21）白血病发生中起致病作用。(2)We在急性髓细胞性白血病中克隆了inv（12）产生的新的TEL/PTPRR嵌合基因。在分子水平上，TEL/PTPRR对野生型TEL具有显性负功能。此外，过表达TEL/PTPRR的UT 7/GM细胞获得了因子非依赖性生长，并且即使在因子去除后也保持了高水平的STAT 3磷酸化。结论：TEL/PTPRR通过抑制TEL和激活STAT 3信号而导致白血病的发生。

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.