Loss of FLJ13639 Expression in Acute Leukemia

描述（由申请人提供）：染色体带13q14异常发生在所有谱系和所有分化阶段的血液恶性肿瘤中。我们发现在急性白血病的染色体带13q14中存在髓系和淋巴系特异性断点簇区（基因染色体癌25:22 22-229,1999）。我们从一个淋巴病例MUTZ5中建立了一个新的细胞系，该细胞系携带单个t（12;13）易位（白血病15:1471-14 74,2001）。这种易位的分子特征使我们能够鉴定出一个名为FLJ13639的新基因，该基因在MUTZ5细胞系中被破坏和丢失。该基因与短链脱氢酶还原酶（SDR）大家族具有同源性。这种新的蛋白质存在于线粒体中。FLJ13639缺失的后果之一是CD24的过度表达。CD24过表达与缺氧状况、急性白血病预后不良以及化疗耐药有关。因此，我们假设FLJ13639表达的缺失导致线粒体功能改变以及CD24表达的增加，从而为白血病细胞提供增殖和侵袭性优势以及一定程度的化疗抗性。添加外源性FLJ13639重组蛋白将导致化疗敏感性增加，并通过改变线粒体功能和CD24的过表达等标志物降低白血病细胞的化疗保护作用。我们的三个假设驱动的特异性目标将如下：特异性目标1：假设：FLJ13639基因在急性白血病中通过遗传和表观遗传事件下调；特异性目的2：假设：FLJ13639- p1蛋白具有脱氢酶活性，参与线粒体中的电子传递。特异性目的3：假设：FLJ13639蛋白的递送诱导急性白血病细胞凋亡。确认FLJ13639缺失在白血病预后中的作用，增加化疗耐药，将引导我们和其他人开发新的预后工具以及新颖，创新的治疗策略。

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.