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 项目摘要 骨髓增生异常综合征(MDS)是美国最常见的肿瘤，具有 惨淡的存活率。此外，每4名MDS患者中就有1人有发展为急性髓系白血病的风险。 (AML)，一种毁灭性的髓系细胞恶性血液病。诊断为MDS的中位年龄为60岁， 因此，干细胞移植在老年人群中不太可能是唯一的治愈方法， 并存疾病。目前使用来那度胺和去甲基化药物的治疗对部分患者有效 MDS患者，但也有副作用，如骨髓抑制。虽然我们对此的理解 在过去的十年中，MDS的病因有了很大的增加，免疫系统在MDS中的作用 其发病机制仍有待进一步研究。因此，针对免疫介质的治疗尚未得到 在MDS中进行了治疗测试。 基于我们对单倍体Riok2表达不足(Riok2/-)和MDS小鼠模型的初步研究 患者样本，我们已经确定了Riok2单倍体功能不全介导的骨髓发育不良与 免疫细胞衍生细胞因子IL-22的诱导。我们的数据显示Riok2单倍体不足与 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T细胞产生的IL-22。此外，Riok2单倍体功能不全介导的细胞周期变化导致 髓系细胞增殖增加。重要的是，RIOK2mRNA在骨髓细胞中的表达减少 来自MDS患者与健康对照组的比较。我们还确定了一个主要的负面影响和5个损失 对红细胞生成产生负面影响的RIOK2功能突变。Riok2/-中Il22的删除不充分 小鼠逆转了红系分化缺陷。我们的研究首次确定了Riok2在人类基因组中的关键功能 调节红细胞生成和免疫系统，两者协同导致骨髓发育不良。 在这项提议中，我们的目标是机械地解开Riok2和IL-22在MDS中的关键作用，并测试其有效性 抑制IL-22对缓解MDS中的贫血和骨髓发育不良的作用。我们将详细评估如何 RIOK2的缺失或突变会影响核糖体的生物发生、红细胞生成、骨髓生成和IL-22的产生。 此外，我们还将测试在Riok2/-小鼠中抑制IL-22是否是缓解 MDS中可见贫血和骨髓发育不良。此外，高通量转录组和蛋白质组分析 在这里提出的Riok2单倍体功能不全介导的MDS这一新的小鼠模型有望揭示 免疫和非免疫的其他治疗靶点，可能成为MDS的靶点 治疗。这一知识应该为设计新一代疗法铺平道路，这种疗法将改善 MDS、AML和贫血患者的疾病转归。靶向IL-22可能会鼓励更有效的免疫- 基于治疗的治疗，无论是作为单一药物治疗，还是与现有治疗相结合，都将改善 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.