Novel Myeloid Cell Transforming Properties of Interleukin-27 Receptor

描述（由申请人提供）：急性髓性白血病（AML）在美国每年折磨着13000名新患者。2007年，这个国家大约有9000人死于这种疾病。彻底了解AML形成所需的信号通路对于开发AML患者急需的治疗方法是必要的。因此，有必要确定导致AML的新突变和信号通路。这些研究的长期目标是确定在白血病发生中起关键作用的新突变和信号通路。这些研究的具体目的是表征I型细胞因子受体白细胞介素-27 （IL27R）受体的转化特性，并确定IL27R对白血病发展的贡献。这是非常令人兴奋的，因为IL27R从未与癌症相关，而I型细胞因子受体最近被证明在各种髓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髓系疾病（包括AML）中发挥未被认识的作用。这项工作的假设是，异常的IL27R信号正在转化，并可能促进白血病的发展。这是基于我们在AML转化基因的新功能基因筛选中鉴定出IL27R。IL27R的转化特性将通过四个具体目标提出的研究进行评估。具体目标1将集中于确定IL27R启动异常信号转导的机制。这将通过对IL27R突变体进行功能分析来在髓细胞中完成，以确定IL27R的哪些区域负责转化。这方面的研究还将确定IL27R二聚化是否在其转化特性中发挥作用。具体目标2的研究将确定IL27R利用哪些JAK和STAT信号通路转化髓细胞。特异性目的3的研究将确定il - 27r在小鼠中的转化特性。这些研究将利用小鼠白血病模型来研究il27r介导的白血病发生。最后，特定目标4的研究将确定IL27R对人类白血病的影响程度。这些研究将包括分析患者AML细胞中IL27R的表达和功能。这些研究是我们最近发现的IL27R的新转化特性的首次研究，并将研究AML的潜在新治疗靶点。公共卫生相关性：AML患者急需的治疗方法的开发在很大程度上依赖于白血病细胞中治疗靶点的识别。这些靶标可以通过表征这些细胞中的不适当信号来确定。本研究旨在研究最近发现的IL27R的致癌特性，并确定AML的潜在治疗干预靶点。

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.