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Multi-faceted Roles of an Atypical Kinase RIOK2 in Erythropoiesis and Myelodyplastic Syndromes

非典型激酶 RIOK2 在红细胞生成和骨髓增生异常综合征中的多方面作用

基本信息

批准号：
10046930
负责人：
LAURIE Hollis GLIMCHER
金额：
$ 17.7万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046930
关键词：
Acute Myelocytic Leukemia Affect Age Anemia Antibodies Aplastic Anemia Aryl Hydrocarbon Receptor Biogenesis Biological Response Modifiers Bone Marrow Bone Marrow Cells CD34 gene CD4 Positive T Lymphocytes Cell Cycle Cells Chromosome Deletion Combined Modality Therapy Data Data Set Defect Development Diagnosis Diamond Dominant-Negative Mutation Dysmyelopoietic Syndromes Embryo Erythroid Erythropoiesis Etiology Expression Profiling Frequencies Functional disorder Generations Genes Genetic Genetic Transcription Hematologic Neoplasms Hematopoiesis Immune Immune Targeting Immune system Immunobiology Immunotherapy Individual Knockout Mice Knowledge Large-Scale Sequencing Lead Link Liquid substance Mediating Messenger RNA Molecular Mus Mutate Mutation Myelogenous Myeloid Cells Myelopoiesis Myelosuppression Neoplasms Open Reading Frames Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphotransferases Production Protein Biosynthesis Protein-Serine-Threonine Kinases Proteome Quality of life Reading Frames Reporting Ribosomes Risk Role S100A9 gene Sampling Shwachman-Diamond syndrome Signal Pathway Stem cell transplant Survival Rate Syndrome T-Lymphocyte Testing Therapeutic United States United States Food and Drug Administration base cell age chromosome 5q loss comorbidity cytokine design efficacy testing erythroid differentiation improved improved outcome interleukin-22 lenalidomide loss of function mRNA Expression mouse model new therapeutic target novel outcome forecast peripheral blood progenitor side effect targeted treatment therapeutic evaluation therapeutic target transcriptome transcriptome sequencing

项目摘要

Multi-faceted Roles of an Atypical Kinase RIOK2 in Erythropoiesis and Myelodysplastic Syndromes Project Summary Myelodysplastic syndromes (MDS) are the most commonly diagnosed neoplasms in the United States with a dismal survival rate. Furthermore, 1 in every 4 MDS patients is at risk of developing Acute Myeloid Leukemia (AML), a devastating hematologic malignancy of myeloid cells. The median age of MDS diagnosis is 60 years, thus making the only cure, stem cell transplantation unlikely in an older demographic with significant associated co-morbidities. Current therapies using lenalidomide and hypomethylating agents are effective in a subset of MDS patients but are also associated with side effects such as myelosuppression. Though our understanding of the etiology of MDS has increased substantially in the past decade, the role of the immune system in MDS pathogenesis is still greatly under explored. Thus, treatments targeting immune mediators have not been therapeutically tested in MDS. Based on our preliminary studies of a mouse model of haploinsufficient Riok2 expression (Riok2+/-) and MDS patient samples, we have identified a link between Riok2 haploinsufficiency-mediated myelodysplasia and induction of the immune cell-derived cytokine IL-22. Our data show that Riok2 haploinsufficiency has a direct negative effect on erythroid progenitor differentiation and an indirect effect by inducing erythropoiesis- suppressive IL-22 from T cells. Additionally, Riok2 haploinsufficiency-mediated cell cycle changes lead to increased proliferation of myeloid cells. Importantly, RIOK2 mRNA expression is decreased in bone marrow cells from MDS patients as compared to healthy controls. We have also identified one dominant negative and 5 loss of function RIOK2 mutations that negatively impact erythropoiesis. Haploinsufficient deletion of Il22 in Riok2+/- mice reversed the erythroid differentiation defect. Our study is the first to identify the critical function of Riok2 in regulating erythropoiesis as well as the immune system, both synergistically leading to myelodysplasia. In this proposal, we aim to mechanistically unravel the critical role of Riok2 and IL-22 in MDS and test the efficacy of IL-22 inhibition on alleviation of the anemia and myelodysplasia seen in MDS. We will assess in detail how loss or mutation of RIOK2 affects ribosome biogenesis, erythropoiesis, myelopoiesis, and IL-22 production. Furthermore, we will also test whether IL-22 inhibition in Riok2+/- mice is a therapeutic strategy to alleviate the anemia and myelodysplasia seen in MDS. Moreover, the high-throughput transcriptome and proteome analyses of this novel mouse model of Riok2 haploinsufficiency-mediated MDS proposed here are expected to reveal additional therapeutic targets, immune as well as non-immune, that can potentially be targeted for MDS treatment. This knowledge should pave the way for devising a new generation of therapies that will improve the outcome of disease for MDS, AML and anemia patients. Targeting IL-22 may encourage more effective immune- based treatments that, either as single agent therapy or in combination with current therapies, will improve the prognosis and quality of life of MDS patients.

非典型激酶 RIOK2 在红细胞生成和骨髓增生异常综合征中的多方面作用项目概要骨髓增生异常综合征 (MDS) 是美国最常诊断的肿瘤，生存率惨淡。此外，每 4 名 MDS 患者中就有 1 名有患急性髓系白血病的风险 (AML)，一种骨髓细胞的毁灭性血液恶性肿瘤。 MDS 诊断的中位年龄为 60 岁，因此，干细胞移植是唯一的治疗方法，不太可能用于与显着相关的老年人群。合并症。目前使用来那度胺和低甲基化药物的疗法对一部分患者有效但MDS患者也与骨髓抑制等副作用相关。虽然我们的理解 MDS 的病因在过去十年中大幅增加，免疫系统在 MDS 中的作用发病机制仍有待进一步探索。因此，针对免疫介质的治疗尚未得到证实。在 MDS 中进行了治疗测试。基于我们对 Riok2 单倍体表达不足 (Riok2+/-) 和 MDS 的小鼠模型的初步研究患者样本中，我们发现了 Riok2 单倍体不足介导的骨髓增生异常与诱导免疫细胞衍生的细胞因子 IL-22。我们的数据表明Riok2单倍体不足有直接的影响对红系祖细胞分化的负面影响以及诱导红细胞生成的间接影响来自 T 细胞的抑制性 IL-22。此外，Riok2 单倍体不足介导的细胞周期变化导致骨髓细胞增殖增加。重要的是，骨髓细胞中 RIOK2 mRNA 表达降低 MDS 患者与健康对照者的比较。我们还确定了 1 个显性阴性和 5 个缺失 RIOK2 功能突变对红细胞生成产生负面影响。 Riok2+/- 中 Il22 的单倍体缺失不足小鼠逆转了红细胞分化缺陷。我们的研究首次确定了 Riok2 在调节红细胞生成和免疫系统，两者协同导致骨髓增生异常。在本提案中，我们的目标是从机制上揭示 Riok2 和 IL-22 在 MDS 中的关键作用并测试其功效 IL-22 抑制可减轻 MDS 中出现的贫血和骨髓增生异常。我们将详细评估如何 RIOK2 的缺失或突变会影响核糖体生物发生、红细胞生成、骨髓生成和 IL-22 产生。此外，我们还将测试 Riok2+/- 小鼠中的 IL-22 抑制是否是缓解 MDS 中可见贫血和骨髓增生异常。此外，高通量转录组和蛋白质组分析这里提出的Riok2单倍体不足介导的MDS新型小鼠模型的研究预计将揭示其他可能针对 MDS 的免疫和非免疫治疗靶点治疗。这些知识应该为设计新一代疗法铺平道路，从而改善 MDS、AML 和贫血患者的疾病结果。以 IL-22 为靶点可能会促进更有效的免疫基础治疗，无论是作为单药治疗还是与当前治疗相结合，都将改善 MDS 患者的预后和生活质量。