NUCLEAR TRANSPORT IN THE GENESIS OF ACUTE LEUKEMIA

描述（申请人的描述）：核运输是一种快速的 推进基础研究领域，获得临床重要性， 最近发现，一种致癌基因可以被染色体激活， 在急性髓性白血病中的重排，编码一个核孔 蛋白 与can重排相关的白血病往往发生在 年轻人，预后相对较差。 其它的核 转运蛋白随后与肿瘤产生相关联。 这些 这些考虑因素迫切需要了解CAN在以下方面的作用： 并提出了更普遍的问题，即异常 核运输在癌症的起因。 两个染色体重排涉及可以被描述：融合 与急性髓细胞性白血病相关的dek基因， 与急性未分化白血病相关的set基因。 在 尽管存在这些关联，而且CAN mRNA在细胞内表达， 优先在造血组织，核运输和作用， CAN尚未在造血细胞中进行研究。 因此，申请人 建议研究CAN的功能及其最常见的融合作用 形式，DEK-CAN，在骨髓细胞系和白血病骨髓细胞中， 患者 假设是，涉及“可以”的重排导致失败， 由于异常率而输入分化所必需的核因子 核运输，导致骨髓细胞的恶性转化。 为了验证他们的假设，他们将稳定地转染HL 60细胞（急性白血病细胞）。 骨髓性白血病细胞系）与表达DEK-CAN的构建体 并观察了NPCs的超微结构、亚细胞层、细胞膜及细胞外基质的变化。 CAN的应用，核进口（标准基板和 与髓样分化相关的转录因子）， 细胞响应于免疫应答而经历髓样分化的能力 体外刺激 相同的参数（除了转录因子和 体外分化）将在来自白血病的骨髓细胞中进行研究。 病人，但不是比较转染，骨髓细胞从 伴有和不伴有易位的急性髓性白血病患者 将比较涉及“can”的情况。 这项研究的最终目的是 确定涉及“可以”导致白血病的易位， 开始了解核转运异常在 癌症的病因。

DESCRIPTION (Applicant's Description): Nuclear transport is a rapidly advancing field of basic research that gained clinical importance with the recent discovery that can, an oncogene activated by chromosomal rearrangements in acute myelogenous leukemia, encodes a nuclear pore protein. Leukemias associated with can rearrangements tend to occur in young people and have a relatively poor prognosis. Several other nuclear transport proteins were subsequently linked to tumor production. These considerations lend urgency to understanding the role of CAN in leukemogenesis and pose the more general question of the role of abnormal nuclear transport in the causation of cancer. Two chromosomal rearrangements involving can have been described: fusion with the dek gene, associated with acute myelogenous leukemia, and fusion with the set gene, associated with acute undifferentiated leukemia. In spite of these associations and the fact that CAN mRNA is expressed preferentially in hematopoietic tissues, nuclear transport and the role of CAN have not been studied in hematopoietic cells. The applicants therefore propose to study the function of CAN and the role of its most common fusion form, DEK-CAN, in a myeloid cell line and in bone marrow cells from leukemic patients. The hypothesis is that rearrangements involving 'can' result in failure to import nuclear factors necessary for differentiation due to an abnormal rate of nuclear transport, leading to malignant transformation of myeloid cells. To test their hypothesis they will stably transfect HL60 cells (an acute myelogenous leukemia cell line) with a construct that expresses the DEK-CAN fusion protein and examine the ultrastructure of the NPCs, the subcellular l o c a lization of CAN, nuclear import (of standard substrate and of transcription factors associated with myeloid differentiation), and the ability of the cells to undergo myeloid differentiation in response to in vitro stimuli. The same parameters (except for transcription factors and in vitro differentiation) will be studied in bone marrow cells from leukemic patients, but instead of comparing transfectants, bone marrow cells from patients with acute myelogenous leukemias with and without translocations involving 'can' will be compared. The ultimate goal of this research is to determine how translocations involving 'can' lead to leukemia, and hence begin to understand the role of nuclear transport abnormalities in the causation of cancer.