Mechanisms in hematopoiesis and leukemogenesis by the transcription factor TEL

TEL对小鼠红细胞白血病MEL细胞造血功能的调控(1)我们证明了TEL能刺激hemin和DMSO化合物诱导的红细胞分化。为了证实TEL在生理环境中的作用，我们将TEL cDNA导入人白血病UT7/GM细胞。TEL能加速促红细胞生成素诱导的红细胞分化，抑制促血小板生成素诱导的巨核细胞分化。这些数据表明，在红细胞/巨核细胞共同祖细胞分化过程中，TEL可能决定细胞命运。(2)我们还研究了电信运营商功能的监管机制。发现TEL被MAP激酶ERK磷酸化。高磷酸化的TEL失去了转录抑制能力和肿瘤抑制功能，对低磷酸化的TEL发挥了显性负向作用。另一方面，TEL基因表达了多种类型的亚型。其中ΔHLH和ΔETS亚型是野生型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，ΔETS亚型在骨髓增生异常综合征衍生白血病中的表达频率增加。(1)已知儿童前b细胞急性淋巴细胞白血病中t（12;21）产生的TEL/AML1主要抑制野生型AML1的功能。我们发现TEL/AML1也抑制野生型TEL的功能。TEL的肿瘤抑制功能的丧失可能在t介导的白血病形成中起致癌变作用（12;21）。(2)克隆了一个由inv（12）在急性髓性白血病中产生的TEL/PTPRR嵌合基因。在分子检测中，TEL/PTPRR比野生型TEL表现为显性阴性。此外，过表达TEL/PTPRR的UT7/GM细胞获得了不依赖于因子的生长，即使在停用因子后也保持了STAT3的高水平磷酸化。我们得出结论，TEL/PTPRR通过使TEL失活和刺激STAT3信号导致白血病。

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.