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

• 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
• 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; 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

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.

异型激酶RIOK2在红细胞生成和骨髓增生综合征中的多方便角色 项目摘要 骨髓增生综合征（MDS）是美国最常见的肿瘤 惨淡的生存率。此外，每4个MDS患者中有1例有患急性髓样白血病的风险 （AML），骨髓细胞的毁灭性血液系统恶性肿瘤。 MDS诊断的中位年龄为60岁， 因此，在较旧的人群中，不太可能使干细胞移植具有显着相关的 合并症。使用Lenalidomide和非甲基化剂的当前疗法在一个子集中有效 MDS患者，但也与诸如骨髓抑制之类的副作用有关。尽管我们对 在过去的十年中，MD的病因已大大增加，免疫系统在MDS中的作用 发病机理仍在大量探索中。因此，针对免疫介质的治疗尚未 在MDS中进行治疗测试。 根据我们对单倍体RIOK2表达（RIOK2 +/-）和MDS的小鼠模型的初步研究 患者样品，我们已经确定了RIOK2单倍弥舒服介导的骨髓增生和 诱导免疫细胞衍生的细胞因子IL-22。我们的数据表明，RIOK2单倍弥补有直接的 对红细胞祖细胞分化和间接作用的负面影响，通过诱导红细胞生成 - T细胞抑制IL-22。此外，RIOK2单倍弥补介导的细胞周期变化导致 髓样细胞的增殖增加。重要的是，骨髓细胞中RIOK2 mRNA表达降低 与健康对照组相比，MDS患者来自MDS患者。我们还确定了一个主要的负面和5个损失 函数RIOK2突变的负面影响促红细胞生成。 RIOK2 +/-中IL22的单倍弥补的删除 小鼠逆转了红系分化缺陷。我们的研究是第一个确定RIOK2在 调节红血病和免疫系统，都协同导致骨髓增生。 在此提案中，我们旨在从机械学上阐明RIOK2和IL-22在MDS中的关键作用并测试功效 IL-22对减轻MDS中贫血和脊髓增生的抑制作用。我们将详细评估如何 RIOK2的丧失或突变会影响核糖体的生物发生，红细胞生成，骨髓病和IL-22产生。 此外，我们还将测试RIOK2 +/-小鼠中的IL-22抑制是否是减轻治疗策略 MDS中可见贫血和脊髓增生。此外，高通量转录组和蛋白质组分析 在这里提出的RIOK2单倍弥补介导的MDS的新型小鼠模型有望揭示 可能针对MD的其他治疗靶标，免疫和非免疫靶标的 治疗。这些知识应该为设计新一代疗法铺平道路，以改善 MDS，AML和贫血患者疾病的结果。靶向IL-22可能会鼓励更有效的免疫力 基于单一药物疗法或与当前疗法结合使用的基于基于的治疗方法将改善 MDS患者的预后和生活质量。