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 基础研究的进步领域，获得了临床重要性 最近发现的CaN，一种由染色体激活的癌基因 急性髓系白血病中的重排，编码一个核孔 蛋白。与CaN重排相关的白血病倾向于发生在 年轻人，预后相对较差。其他几个核项目 运输蛋白随后被认为与肿瘤的产生有关。这些 考虑因素使理解CAN的作用变得迫切 白血病的发生和提出了更一般的问题，异常的作用 核运输在癌症病因中的作用。 可以描述两种涉及的染色体重排：融合 与dek基因相关的急性髓系白血病与融合 带有SET基因，与急性未分化白血病有关。在……里面 尽管存在这些联系，但事实是，CaN mRNA表达 优先在造血组织中，核转运和作用 可能还没有在造血细胞中研究过。因此，申请者 建议研究CAN的功能及其最常见的融合作用 在髓系细胞系和白血病的骨髓细胞中形成dek-can 病人。 这个假设是，涉及“可能”的重新安排导致未能 由于异常率，进口核因子是分化所必需的 核运输，导致髓系细胞恶性转化。 为了验证他们的假设，他们将稳定地转染HL60细胞(急性 具有表达dek-can的构建物) 融合蛋白和超微结构检测鼻咽癌细胞亚细胞L 罐头国产化、核进口(标准基材和 与髓系分化相关的转录因子)，以及 细胞对In的反应经历髓系分化的能力 体外刺激。相同的参数(除转录因子和 体外分化)将在白血病的骨髓细胞中进行研究 患者，但不是比较转染者，而是来自 伴有和不伴有易位的急性髓系白血病患者 涉及“can”的词将被比较。这项研究的最终目的是 确定涉及“可能”的易位如何导致白血病 开始了解核运输异常在 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.