Novel Myeloid Cell Transforming Properties of Interleukin-27 Receptor

IL-27 受体的新型骨髓细胞转化特性

• 批准号: 8109284
• 负责人: GARY W REUTHER
• 金额: $ 33.61万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8109284
• 关键词: Acute; Acute Myelocytic Leukemia; Adult; Affect; Animal Model; Biological Models; Cancer Center; Cells; Chromosomal translocation; Chronic Myeloid Leukemia; Clinical; Core Facility; Country; Cytokine Receptors; Data; Development; Dimerization; Disease; Environment; Genes; Genetic; Genetic Screening; Gleevec; Goals; Growth; Health; Hematology; Hematopoietic; Human; IL3RA gene; Imatinib mesylate; Interleukin Receptor; Interleukins; Knowledge; Laboratories; Lead; Leukemic Cell; Link; Malignant - descriptor; Malignant Neoplasms; Mammalian Cell; Mediating; Molecular; Mus; Mutation; Myelogenous; Myeloid Cells; Myeloid Leukemia; Myeloproliferative disease; Oncogenes; Oncogenic; Outcomes Research; Pathway interactions; Patients; Play; Point Mutation; Positioning Attribute; Property; Protein Tyrosine Kinase; Proteins; Receptor Activation; Research; Research Personnel; Role; STAT protein; Sampling; Screening procedure; Signal Pathway; Signal Transduction; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Tretinoin; Work; base; cancer type; cell growth; cell transformation; cytokine; experience; human MPL protein; in vivo; innovation; interest; knock-down; leukemia; leukemogenesis; mouse model; mutant; new therapeutic target; novel; programs; receptor; success; therapeutic target; tumorigenic

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.

描述（由申请人提供）：急性髓性白血病（AML）每年在美国折磨13，000名新患者。2007年，这个国家大约有9,000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，有必要确定有助于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。这些研究的具体目标是表征白细胞介素-27受体（IL 27 R）（一种I型细胞因子受体）的转化特性，并确定IL 27 R对白血病发展的贡献。这是非常令人兴奋的，因为IL 27 R从未与癌症相关，并且I型细胞因子受体最近已被证明在各种骨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包括AML在内的骨髓疾病中发挥未被认识的作用。这项工作的假设是，异常的IL 27 R信号转导是转化的，可以促进白血病的发展。这是基于我们在AML中转化基因的新功能遗传筛选中鉴定IL 27 R。IL 27 R的转化特性将通过四个具体目标中提出的研究进行评估。具体目标1将集中于确定IL 27 R启动异常信号转导的机制。这将在骨髓细胞中通过对IL 27 R突变体进行功能分析来完成，以确定IL 27 R的哪些区域负责转化。为此目的的研究还将确定IL 27 R二聚化是否在其转化特性中起作用。具体目标2中的研究将确定IL 27 R利用哪种JAK和STAT信号传导途径来转化骨髓细胞。具体目标3中的研究将确定小鼠中IL 27 R的转化性质。这些研究将利用白血病的小鼠模型来研究IL 27 R介导的白血病发生。最后，具体目标4中的研究将确定IL 27 R对人白血病的贡献程度。这些研究将包括分析来自患者的AML细胞中IL 27 R的表达和功能。这些研究首次研究了我们最近发现的IL 27 R的新转化特性，并将研究AML的潜在新治疗靶点。公共卫生关系：AML患者急需的治疗方法的开发在很大程度上取决于白血病细胞中治疗靶点的鉴定。这些目标可以通过表征这些细胞中的不适当信号来确定。该提案研究了最近发现的IL 27 R的致癌特性，并将确定AML潜在治疗干预的靶点。