MOLECULAR PATHOLOGY OF ACUTE PROMYELOCYTIC LEUKEMIA

描述：（改编自研究者摘要）在过去的几年里， 在理解脑出血的分子病理学方面已经取得了重大进展， 急性早幼粒细胞白血病（APL）。细胞培养和动物模型都支持 由t（15;17）产生的PML-RARA融合蛋白是 负责APL的开发。然而，我们的研究表明， PML是一种在APL中被破坏的生长和转化抑制因子， 也参与了APL的发病机制。我们在上一次会议期间的主要重点是 基金期间的目的是了解PML的生物学功能。几个新 这些研究得出了一些结果。(a)PML在调节 细胞周期进程和凋亡。PML的这些重要属性是 刚刚开始出现以及PML调节细胞的分子机制 细胞周期进展和细胞凋亡还不清楚。(b)我们的研究表明 PML是细胞周期蛋白依赖性激酶的底物，这进一步支持了 PML在细胞周期控制中的作用。PML的磷酸化如何影响生长 抑制和凋亡是未知的。(c)我们的研究提供了重要的 了解PML的转录调控功能。我们发现PML 抑制参与G1到S的靶基因的Sp1依赖性转录 PML抑制NF κ B靶点的反式激活 发起人。(d)PML募集组蛋白去乙酰化酶并沉默 通过启动子的去乙酰化作用来修饰靶基因。我们建议继续追查 具体目的如下：（1）研究PML对细胞增殖的调控机制， 细胞周期进程待检验假设：PML调节细胞周期 通过影响胃肠道的反式激活， 参与G1/S检查点的基因。(2)研究PML的分子基础 诱导凋亡。待检验的假设：PML通过（i）诱导细胞凋亡 NF κ B的抗凋亡作用的去抑制;（ii）诱导NF κ B的表达， p53;和（iii）与Bax的功能性相互作用。(3)研究PML 磷酸化及其生物学意义。待检验的假设： PML蛋白的磷酸化和去磷酸化起重要作用 在细胞周期进程、凋亡和转录的调节中 调控本提案中概述的研究将提供重要的 了解细胞周期调控和凋亡的信息。结果 从这些研究中获得的信息将进一步扩大我们对 急性早幼粒细胞白血病的分子病理学

DESCRIPTION: (Adapted from the investigator's abstract) In the past few years, significant progress has been made in understanding the molecular pathology of acute promyelocytic leukemia (APL). Both cell culture and animal models support the suggestion that the PML-RARA fusion protein resulting from the t(15;17) is responsible for the development of APL. However, our studies indicate that loss of function of PML, a growth and transformation suppressor disrupted in APL may also contribute to the pathogenesis of APL. Our major focus during the previous funding period was to understand the biological function of PML. Several new findings have resulted from these studies. (a) PML plays a role in regulating cell cycle progression and apoptosis. These important properties of PML are just beginning to emerge and the molecular mechanism of how PML regulates cell cycle progression and apoptosis is not well understood. (b) Our studies suggest that PML is a substrate of cyclin-dependent kinases, this further supporting a role for PML in cell cycle control. How phosphorylation of PML affects growth suppression and apoptosis is unknown. (c) Our studies provided significant insight into the transcriptional regulatory function of PML. We found that PML represses Sp1-dependent transcription of target genes involved in the G1 to S transition, and that PML represses transactivation of NFkappaB target promoters. (d) PML recruits histone deacetylase and silences transcription of target genes by deacetylation of the promoter. We propose to continue to pursue the following specific aims: (1) to study the mechanism of PML regulation of cell cycle progression. Hypothesis to be tested: PML regulates cell cycle progression by inducing a GI arrest through its effects on transactivation of genes involved in the G1/S checkpoint. (2) To study the molecular basis of PML induced apoptosis. Hypothesis to be tested: PML induces apoptosis by (i) de-repression of the antiapoptotic effects of NFKB; (ii) induced expression of p53; and (iii) functional interaction with Bax. (3) To study PML phosphorylation and the biologic significance. Hypothesis to be tested: Phosphorylation and dephosphorylation of the PML protein play an important role in the regulation of cell cycle progression, apoptosis, and transcription regulation. Studies outlined in this proposal will provide important information toward understanding cell cycle regulation and apoptosis. Results obtained from these studies will further expand our knowledge in understanding the molecular pathology of acute promyelocytic leukemia.