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

非典型激酶RIOK 2在红细胞生成和骨髓增生异常综合征中的多方面作用 项目摘要 骨髓增生异常综合征（MDS）是美国最常见的肿瘤， 存活率很低此外，每4例MDS患者中就有1例有发生急性髓性白血病的风险 (AML)是一种毁灭性的骨髓细胞恶性血液病。MDS诊断的中位年龄为60岁， 因此，唯一的治疗方法，干细胞移植不太可能在老年人口中进行， 合并症目前使用来那度胺和低甲基化剂的疗法在以下亚组中是有效的： 骨髓增生异常综合症患者，但也与骨髓抑制等副作用有关。尽管我们对 MDS的病因在过去十年中显著增加，免疫系统在MDS中的作用 发病机制仍在探索之中。因此，靶向免疫介质的治疗尚未被广泛应用。 在MDS中进行治疗测试。 基于我们对Riok 2单倍表达不足（Riok 2 +/-）和MDS的小鼠模型的初步研究， 患者样本中，我们已经确定了Riok 2单倍体缺陷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。我们的数据显示Riok 2单倍不足与 对红系祖细胞分化的负面影响和通过诱导红细胞生成的间接影响， 抑制性IL-22从T细胞。此外，Riok 2单倍体不表达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RIOK 2 mRNA表达降低 MDS患者与健康对照组相比。我们还确定了一个显性负面和5个损失 对红细胞生成有负面影响的RIOK 2功能突变。Riok 2 +/-中Il 22的单倍缺失不足 小鼠逆转了红系分化缺陷。我们的研究是第一个确定Riok 2在 调节红细胞生成以及免疫系统，两者协同导致骨髓增生异常。 在这项提议中，我们的目标是从机制上阐明Riok 2和IL-22在MDS中的关键作用，并测试其疗效。 IL-22抑制对缓解MDS中所见的贫血和骨髓增生异常的作用。我们将详细评估 RIOK 2的缺失或突变影响核糖体生物发生、红细胞生成、骨髓生成和IL-22的产生。 此外，我们还将测试Riok 2 +/-小鼠中的IL-22抑制是否是减轻IL-22抑制的治疗策略。 骨髓增生异常综合征中的贫血和骨髓增生异常。此外，高通量转录组和蛋白质组分析 本文提出的这种新型Riok 2单倍性介导的MDS小鼠模型的研究， 其他治疗靶点，免疫和非免疫，可能成为MDS的靶点 治疗这些知识应该为设计新一代的治疗方法铺平道路， MDS、AML和贫血患者的疾病结局。靶向IL-22可以促进更有效的免疫- 作为单一药物治疗或与当前治疗组合， MDS患者的预后和生活质量。

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.