Loss of FLJ13639 Expression in Acute Leukemia

描述（由申请人提供）：染色体带13 q14的缺失发生在所有谱系和所有分化阶段的恶性血液病中。我们发现急性白血病染色体带13 q14内存在骨髓和淋巴特异性断点簇区域（Genes Chromosome Cancer 25：222-229，1999）。我们从一个淋巴病例MUTZ 5中建立了一个新的细胞系，该细胞系携带单个t（12;13）易位（Leukemia 15：1471-1474，2001）。这种易位的分子特征使我们能够鉴定出一种名为FLJ 13639的新基因，该基因在MUTZ 5细胞系中被破坏并丢失。该基因与短链脱氢酶还原酶（SDR）大家族具有同源性。这种新的蛋白质定位于线粒体中。FLJ 13639缺失的后果之一是CD 24的过度表达。CD 24过表达与急性白血病的缺氧条件和不良预后以及化疗耐药性有关。因此，我们假设FLJ 13639表达的缺失导致线粒体功能改变以及CD 24表达的增加，这为白血病细胞提供了增殖和侵袭优势以及一定程度的化疗抗性。外源FLJ 13639重组蛋白的添加将导致化学敏感性的增加，并通过改变线粒体功能和CD 24的过表达以及其他标志物来减少向白血病细胞提供的化学保护。我们的三个假设驱动的具体目标如下：具体目标1：假设：FLJ 13639基因在急性白血病中通过遗传和表观遗传事件下调;具体目标2：假设：FLJ 13639-P1蛋白具有脱氢酶活性，并参与线粒体中的电子传递;具体目标3：假设：FLJ 13639蛋白诱导急性白血病细胞凋亡FLJ 13639缺失在白血病预后、化疗耐药性增加中的作用的确认，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.