Loss of FLJ13639 Expression in Acute Leukemia

描述(申请人提供)：染色体13q14带异常出现在所有血液病的所有谱系和分化的所有阶段。我们发现在急性白血病(基因染色体癌25：222-229,1999)的染色体带13q14内存在髓系和淋巴系特异的断裂点聚集区。我们从其中一个淋巴样病例中建立了一个新的细胞系MUTZ5，该细胞系携带单个t(12；13)易位(白血病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FLJ13639的新基因，该基因在MUTZ5细胞系中被破坏并丢失。该基因与短链脱氢酶还原酶(SDR)大家族有同源性。这种新的蛋白质定位在线粒体中。失去FLJ13639的后果之一是CD24的过度表达。CD24的过度表达与急性白血病的低氧状态和预后不良以及化疗耐药有关。因此，我们推测，FLJ13639的表达缺失会导致线粒体功能的改变以及CD24表达的增加，这为白血病细胞提供了增殖和侵袭优势，并对化疗产生了一定程度的耐药性。外源性FLJ13639重组蛋白的加入将导致化疗敏感性的增加，并通过改变线粒体功能和CD24的过度表达等标志降低对白血病细胞的化学保护。我们的三个假设驱动的特定目标如下：特定目标1：假设：FLJ13639基因在急性白血病中受到遗传和表观遗传事件的下调；特定目标2：假设：FLJ13639-P1蛋白具有脱氢酶活性，并参与线粒体的电子传递；特定目标3：假设：转导FLJ13639蛋白诱导急性白血病细胞凋亡。随着FLJ13639缺失在白血病预后中作用的确认，化疗耐药的增加应该会引导我们和其他人开发新的预后工具以及新的、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.