Loss of FLJ13639 Expression in Acute Leukemia

急性白血病中 FLJ13639 表达缺失

• 批准号: 7211994
• 负责人: LIONEL J COIGNET
• 金额: $ 28.16万
• 依托单位: ROSWELL PARK CANCER INSTITUTE CORP
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-18 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211994
• 关键词: acute leukemia; apoptosis; birth; cell line; chromosomes; electron transport; epigenetics; genes; genetics; lead; leukemia; mitochondria; prognosis; proteins; recombinant proteins; role

DESCRIPTION (provided by applicant): Abnormalities of chromosome band 13q14 occur in hematologic malignancies of all lineages and at all stages of differentiation. We showed the presence of myeloid- and lymphoid-specific breakpoint cluster regions within chromosome band 13q14 in acute leukemia (Genes Chromosome Cancer 25:222-229, 1999). We established a new cell line from one of the lymphoid cases, MUTZ5, that carries a single t(12;13) translocation (Leukemia 15:1471-1474, 2001). The molecular characterization of this translocation allowed us to identify a new gene called FLJ13639 that is disrupted and lost in the MUTZ5 cell line. This gene shares homologies with the large family of short-chain dehydrogenase reductase (SDR). This new protein localizes in the mitochondria. One of the consequences of the loss of FLJ13639 is the over-expression of CD24. CD24 over-expression has been linked with hypoxic conditions and poor prognostic in acute leukemia as well as chemoresistance. We therefore hypothesize that loss of the FLJ13639 expression leads to altered mitochondrial function as well as increase in CD24 expression that provides leukemia cells with a proliferation and invasiveness advantage as well as a certain degree of resistance to chemotherapy. The addition of exogenous FLJ13639 recombinant protein would lead to an increase in chemosensitivity and reduce chemoprotection provided to leukemia cells by altered mitochondrial function and over-expression of CD24, among other markers. Our three hypothesis-driven Specific aims will be as follows: Specific Aim 1: Hypothesis: The FLJ13639 gene is down regulated in acute leukemia by both genetic and epigenetic events; Specific Aim 2: Hypothesis: The FLJ13639-P1 protein has a dehydrogenase activity and is involved in electron transport in mitochondria and Specific Aim 3: Hypothesis: Delivery of FLJ13639 protein induces apoptosis in acute leukemia cells. Confirmation of the role of the loss of FLJ13639 in leukemia prognosis, increase of chemo resistance should lead us and others, to develop new prognostic tools as well as novel, innovative therapeutic strategies.

描述（由申请人提供）：染色体条带13Q14的异常发生在所有谱系的血液恶性肿瘤中，并且在分化的所有阶段。我们展示了急性白血病中染色体带13q14中髓样和淋巴特异性断裂点簇区的存在（基因染色体癌症25：222-229，1999）。我们从淋巴样病例之一MUTZ5建立了一个新的细胞系，该病例含有单个T（12; 13）易位（白血病15：1471-1474，2001）。这种易位的分子表征使我们能够识别一个称为FLJ13639的新基因，该基因在MUTZ5细胞系中被破坏和丢失。该基因与大型短链脱氢酶还原酶（SDR）共享同源性。该新蛋白质位于线粒体中。 FLJ13639丢失的后果之一是CD24的过表达。 CD24的过表达与低氧条件和急性白血病和化学耐药性的预后不良有关。因此，我们假设FLJ13639表达的丧失会导致线粒体功能改变，以及CD24表达的增加，这为白血病细胞提供了增殖和侵入性优势以及对化学疗法的一定程度的抗性。外源性FLJ13639重组蛋白的添加将导致化学敏感性升高，并通过改变CD24的线粒体功能和过度表达的CD24等标记物以及其他标记物的过表达来减少对白血病细胞提供的化学保护。我们的三个假设驱动的特定目的将如下：特定目的1：假设：FLJ13639基因受遗传和表观遗传事件的调节在急性白血病中的调节；具体目的2：假设：FLJ13639-P1蛋白具有脱氢酶活性，并参与线粒体中的电子转运和特定目标3：假设：FLJ13639蛋白的递送可诱导急性白血病细胞中的凋亡。确认FLJ13639在白血病预后的作用，化学耐药性的增加应该引导我们和其他人开发新的预后工具以及新颖的创新性治疗策略。