Role of MN1 TEL and TEL in Leukemogenesis

描述：（由申请人提供）TEL（ETV 6）是 造血系统恶性肿瘤和某些实体瘤中的染色体易位。 与骨髓增生性疾病相关的复发性t（12;22） 和急性髓性白血病，导致MN 1-TEL融合基因的产生 其中编码转录的N-末端区域的序列 因子TEL被替换为几乎整个编码序列， 转录辅激活因子MN 1。MN 1-TEL可以转化成纤维细胞，并且最近 研究结果表明，这种融合蛋白增加了细胞的增殖率， 体外培养的原始造血祖细胞。然而，小鼠移植 用含MN 1-TEL的逆转录病毒转导骨髓细胞， 致死性照射受体不会导致明显的血液学 异常或白血病。这一结果表明，继发性遗传病变 必须与MN 1-TEL协同转化原始造血祖细胞。 因此，逆转录病毒介导的MN 1-TEL-表达骨髓细胞 将进行鉴定那些与MN合作的遗传病变， 1-TEL诱导白血病（特异性目的1）。早期的工作 鉴定了一种新的TEL同源物，TEL 2，其主要在人类中表达。 胎儿肝脏和骨髓细胞。TEL 2具有广泛的序列同源性， 尽管这两种蛋白质通过其尖结构域形成寡聚体， 通过相同的DNA识别序列抑制转录， 不同的生物活动。值得注意的是，TEL 2的过表达刺激了细胞的增殖。 小鼠造血祖细胞的体外增殖。因为遗传 有证据表明，TEL作为肿瘤抑制剂，实验将测试 假设TEL的丢失导致TEL：TEL 2的比率改变， TEL 2：TEL 2寡聚体，并且这种改变直接导致TEL 2：TEL 2寡聚体的增加。 受影响细胞的增殖（具体目标2）。综合起来， 拟议的研究应提供深入了解参与的途径， MN 1-TEL相关白血病及其抑瘤机制的 在这些研究中产生的鼠模型应该是研究 开发T（12;22）相关骨髓疾病的新疗法。

DESCRIPTION: (provided by applicant) TEL (ETV6) is a frequent target of chromosomal translocations in hematopoietic malignancies and some solid tumors. The recurrent t(1 2;22), which is associated with myeloproliferative disorders and acute myeloid leukemia, results in the creation of the MN 1-TEL fusion gene in which the sequence encoding the N-terminal region of the transcription factor TEL is replaced by almost the entire coding sequence of the transcriptional coactivator MN1. MN1-TEL can transform fibroblasts, and recent findings suggest that this fusion protein increases the proliferation rate of primitive hematopoietic progenitors in vitro. However, transplantation of mouse bone marrow cells transduced with an MN1-TEL--containing retrovirus into lethally irradiated recipients does not result in overt hematologic abnormalities or leukemia. This result suggests that secondary genetic lesions must cooperate with MN1-TEL to transform primitive hematopoietic progenitors. Therefore, retroviral rnutagenesis of MN1-TEL--expressing boneS marrow cells will be performed to identify those genetic lesions that cooperate with MN 1-TEL in the induction of leukemia (Specific Aim 1). Earlier work has identified a novel TEL homolog, TEL2, which is primarily expressed in human fetal liver and bone marrow cells. TEL2 has extensive sequence homology with TEL; although both proteins form oligomers via their pointed domains and repress transcription through the same DNA recognition sequence, they have distinct biological activities. Notably, overexpression of TEL2 stimulates the proliferation of murine hematopoietic progenitors in vitro. Because genetic evidence suggests that TEL acts as tumor suppressor, experiments will test the hypothesis that the loss of TEL results in an altered ratio of TEL:TEL2 to TEL2:TEL2 oligomers and that this alteration directly results in increased proliferation of affected cells (Specific Aim 2). Together the results of the proposed studies should provide insight into the pathways involved in MN1-TEL-associated leukemia and TEL's mechanism of tumor suppression. The murine models generated in these studies should be valuable tools in the development of new therapies for t(1 2;22)-associated myeloid diseases.