Oncogene-Induced Evasion from Apoptosis

描述（由申请人提供）：逃避细胞凋亡是癌症进展研究较少的标志之一。Bcr-Abl癌基因促进造血细胞的非依赖于嘌呤的生长，这导致其增强的增殖和逃避凋亡。这一过程最终导致慢性粒细胞白血病（CML）。我们最近报道，Bcr-Abl表达促进逃避体外凋亡的一种机制是通过抑制FOXO 3a依赖的几种促凋亡因子的转录，包括TRAIL，以及Bim和Hrk。本提案的总体目标是阐明FOXO 3a及其下游靶点TRAIL、Bim和Hrk在Bcr-Abl诱导的逃避凋亡中的生理作用及其在体内Bcr-Abl诱导的骨髓增生性疾病（MPD）中的参与。正如本提案中所详述的，我们假设FOXO 3a依赖性Bcr-Abl诱导的TRAIL、Bim和Hrk调节是体内调节Bcr-Abl致瘤活性的新机制。此外，我们证实，TRAIL，Bim和Hrk的协调调节促进Bcr-Abl诱导的白血病。最后，我们提出，Bcr-Abl支持逃避凋亡，通过煽动FOXO 3a的蛋白酶体降解。因此，我们假设靶向FOXO 3a可能是诱导Bcr-Abl转化细胞肿瘤选择性凋亡的治疗策略。该提案的具体目标是：1）确定FOXO 3 a转录因子活性的生物学意义和随后对TRAIL表达的调节在促进Bcr-Abl诱导的造血细胞转化中的生物学意义，2）确定Bcr-Abl是否也以FOXO 3 a依赖性方式调节Bim和Hrk表达作为白血病造血细胞中凋亡逃避的机制，3）研究蛋白酶体途径在Bcr-Abl介导的FOXO 3a转录因子下调中的作用。我们将利用多种方法进行这些研究，包括分子生物学、细胞生物学、小鼠致瘤性模型和Bcr-Abl诱导的小鼠白血病模型。总之，这些研究将导致更好地了解白血病发生的机制，并为CML治疗提供新的分子靶点。鉴于对目前使用的STI-571疗法的耐药性正在成为一个常见问题，寻找新的靶点尤为关键。

DESCRIPTION (provided by applicant): Evasion from apoptosis is one of the less investigated hallmarks of cancer progression. The Bcr-Abl oncogene facilitates cytokine-independent growth of hematopoietic cells, which results in their enhanced proliferation and evasion from apoptosis. This process ultimately leads to chronic myeloid leukemia (CML). We recently reported that one mechanism by which Bcr-Abl expression promotes evasion from apoptosis in vitro is through the inhibition of FOXO3a-dependent transcription of several pro-apoptotic factors including TRAIL, as well as Bim and Hrk. The overall objective of this proposal is to elucidate the physiological role of FOXO3a and its downstream targets, TRAIL, Bim and Hrk, in Bcr-Abl-induced evasion from apoptosis and their involvement in Bcr-Abl-induced myeloproliferative disorders (MPD) in vivo. As is detailed in this proposal, we hypothesize that FOXO3a-dependent, Bcr-Abl-induced regulation of TRAIL, Bim and Hrk is a novel mechanism for regulating the tumorigenic activity of Bcr-Abl in vivo. Additionally, we posit that coordinate regulation of TRAIL, Bim and Hrk promotes Bcr-Abl-induced leukemia. Finally, we propose that Bcr-Abl supports evasion from apoptosis by instigating the proteasomal degradation of FOXO3a. Therefore, we hypothesize that targeting FOXO3a may be a therapeutic strategy to induce tumor-selective apoptosis in Bcr-Abl transformed cells. The Specific Aims of this proposal are: 1) to determine the biological significance of FOXO3a transcription factor activity and consequent regulation of TRAIL expression in promoting Bcr-Abl-induced transformation of hematopoietic cells, 2) to determine whether Bcr-Abl also regulates Bim and Hrk expression in a FOXO3a dependent manner as a mechanism for apoptotic evasion in leukemic hematopoietic cells, 3) to determine the role of the proteasomal pathway in Bcr-Abl-mediated down-regulation of FOXO3a transcription factor. We will utilize diverse approaches to carry out these studies including molecular biology, cell biology, murine models for tumorigenicity and murine model for Bcr-Abl-induced leukemia. Taken together, these studies will lead to a better understanding of the mechanisms involved in leukemogenesis in general and to the characterization of novel molecular targets for treatment of CML. Finding a novel target is especially critical given that resistance to the currently used STI-571 therapy is emerging as a common problem.