Novel Myeloid Cell Transforming Properties of Interleukin-27 Receptor

描述(申请人提供)：急性髓系白血病(AML)在美国每年新增13,000名患者。2007年，美国约有9000人死于这种疾病。为了开发AML患者急需的治疗方法，有必要彻底了解AML形成所需的信号通路。因此，有必要确定导致AML的新的突变和信号通路。这些研究的长期目标是确定在白血病发生中发挥关键作用的新的突变和信号通路。这些研究的具体目的是鉴定白细胞介素27受体(IL27R)的转化特性，并确定IL27R在白血病发生发展中的作用。这是非常令人兴奋的，因为IL27R从未与癌症有关，而且I型细胞因子受体最近被证明在各种髓系细胞疾病中发挥重要作用。这表明这些细胞因子受体可能在包括急性髓系白血病在内的髓系疾病中发挥着未被认识的作用。这项工作的假设是，异常的IL27R信号正在转化，并可能有助于白血病的发展。这是基于我们在AML转化基因的一个新的功能性遗传筛查中发现了IL27R。将通过四个具体目标提出的研究来评估IL27R的转化特性。具体目标1将集中于确定IL27R启动异常信号转导的机制。这将在髓系细胞中完成，方法是对IL27R突变体进行功能分析，以确定IL27R的哪些区域负责转化。这一目标的研究还将确定IL27R二聚化是否在其转化特性中发挥作用。针对特定目标2的研究将确定IL27R利用哪些JAK和STAT信号通路来转化髓系细胞。特异性靶点3的研究将确定IL27R在小鼠体内的转化特性。这些研究将利用白血病的小鼠模型来研究IL27R介导的白血病发生。最后，针对特定目标4的研究将确定IL27R在人类白血病中的作用程度。这些研究将包括分析IL27R在患者AML细胞中的表达和功能。这项研究是首次研究我们最近发现的IL27R的新的转化特性，并将探索AML潜在的新治疗靶点。公共卫生相关性：急性髓细胞白血病患者急需的治疗方法的发展在很大程度上取决于白血病细胞中治疗靶点的确定。这些目标可以通过表征这些细胞中的不适当信号来确定。这项提案调查了最近发现的IL27R的致癌特性，并将确定AML潜在治疗干预的靶点。

DESCRIPTION (provided by applicant): Acute myeloid leukemia (AML) afflicts 13,000 new patients in the U.S. each year. About 9,000 people in this country died of this disease in 2007. A thorough understanding of the signaling pathways required for AML formation is necessary in order to develop much needed therapeutic treatments for AML patients. Therefore, there is a need to identify novel mutations and signaling pathways that contribute to AML. The long-term objective of these studies is to identify new mutations and signaling pathways that play critical roles in leukemogenesis. The specific objectives of these studies are to characterize the transforming properties of the receptor for interleukin-27 (IL27R), a type I cytokine receptor, and to determine the contribution of IL27R to the development of leukemia. This is very exciting because IL27R has never been linked to cancer and type I cytokine receptors have recently been shown to play important roles in various myeloid cell disorders. This suggests these cytokine receptors may play unappreciated roles in myeloid diseases including AML. The hypothesis for this work is that aberrant IL27R signaling is transforming and can contribute to leukemia development. This is based on our identification of IL27R in a novel functional genetic screen of transforming genes in AML. The transforming properties of IL27R will be evaluated through studies proposed in four specific aims. Specific aim 1 will focus on determining the mechanism by which IL27R initiates aberrant signal transduction. This will be done in myeloid cells by performing functional analyses on IL27R mutants to determine which regions of IL27R are responsible for transformation. Studies in this aim will also determine if IL27R dimerization plays a role in its transforming properties. Studies in specific aim 2 will determine which JAK and STAT signaling pathways are utilized by IL27R to transform myeloid cells. Studies in specific aim 3 will determine the transforming properties of IL27R in mice. These studies will utilize mouse models for leukemia to study IL27R-mediated leukemogenesis. Finally, studies in specific aim 4 will determine the extent to which IL27R contributes to human leukemia. These studies will include analyzing IL27R expression and function in AML cells from patients. The proposed studies are the first to investigate the novel transforming properties of IL27R, which we recently discovered, and will investigate potential novel therapeutic targets for AML. PUBLIC HEALTH RELEVANCE: The development of much needed treatments for AML patients is largely dependent on the identification of therapeutic targets in leukemic cells. These targets can be determined through characterizing inappropriate signals in these cells. This proposal investigates the recently identified oncogenic properties of IL27R and will identify targets for potential therapeutic intervention for AML.