Molecular Mechanisms of MDS pathogenesis with aging

项目总结/摘要 在过去的十年中，已经做出了重大努力来了解发展和复杂性， 骨髓增生异常综合征（MDS），导致识别复发性突变基因， 临床、预后和治疗意义。然而，这还没有被翻译成有效的。 治疗。MDS可以由一小群疾病起始细胞引起，这些细胞不能被 传统疗法。对调节这些疾病的分子途径的更好理解 启动干细胞对于未来治愈性疗法的发展至关重要。有几个因素共同作用于 诱导恶性细胞进化。使用3种MDS小鼠模型（β-连环蛋白诱导的，NUP 98-HOXD 13-H 0XD）， 诱导的MDS模型和PU.1UREhetMsh2-/-诱导的MDS模型）和患者细胞（MDS和配对MDS， 转化的AML），我们已经鉴定了与MDS诱导高度相关的转录标记， 疾病转化该特征包括核孔蛋白（NUPs）家族成员的表达降低 与MDS细胞相比。与健康人相比，NUPs表达在MDS细胞中也下调。 在人类HSC中，与DNMT 3A突变呈负相关，DNMT 3A突变在年龄相关的克隆中很突出。 造血（AML），从以前的MDS转化的AML病例。在小鼠和人类iPSC模型中， MDS，降低NUPs表达诱导MDS细胞转化为AML原始细胞。我们的目标是 本申请的目的是全面检查NUP途径在MDS诱导中的作用， 克隆性造血和炎症的衰老相关因素以及MDS干细胞动力学和 确定其行动的驱动因素和机制。为了实现这一点，我们将定义 NUPs下调通过其影响MDS中疾病起始干细胞的生长; 确定NUPs表达降低对MDS随着衰老和衰老而启动的要求- 炎症和炎症应激的相关因素;并确定NUPs如何促进克隆异质性 通过定义NUP相关MDS演变的遗传、分子和转录机制， 衰老这些研究将确定机制和分子是重大贡献者MDS 发病机制，并且其可以是治疗性和预防性靶向的。

Project Summary/Abstract In the last decade, significant efforts have been made to understand the development and complexity of Myelodysplastic syndromes (MDS), leading to the identification of recurrently mutated genes with well-defined clinical, prognostic, and therapeutic implications. However, this has not been translated yet in effective treatments. MDS can arise from a small population of disease-initiating cells that are not eliminated by conventional therapies. An improved understanding of the molecular pathways that regulate these disease initiating stem cells is paramount for the development of future curative therapies. Several factors converge to induce evolution of malignant cells. Using 3 mouse models of MDS (the β-catenin-induced, the NUP98-HOXD13- induced and the PU.1UREhetMsh2–/– -induced MDS models) and patient cells (MDS and paired MDS to transformed AML) we have identified a transcriptional signature that is highly associated with MDS induction and disease transformation. This signature comprises decreased expression of Nucleoporin (NUPs) family members in AML as compared to MDS cells. NUPs expression is also downregulated in MDS cells as compared to healthy HSCs in humans and inversely correlates with DNMT3A mutations, that are prominent in age-related clonal hematopoiesis (ARCH), in AML cases transformed from previous MDS. In mouse and human iPSC models of MDS, decreasing NUPs expression induces transformation of MDS cells to AML blasts. Our goal in this application is to comprehensively examine the role of the NUP pathway in the induction of MDS from aging related factors of clonal hematopoiesis and inflammation and in MDS stem cell dynamics and identify the driving factors and mechanisms of their actions. To achieve this, we will define the mechanism through which NUPs downregulation affects the growth of disease initiating stem cells in MDS; determine the requirement of a decrease in NUPs expression for MDS initiation with aging and aging- related factors of ARCH and inflammatory stress; and determine how NUPs promote clonal heterogeneity by defining the genetic, molecular and transcriptional mechanisms of NUP-related MDS evolution with aging. These studies will identify mechanisms and molecules that are significant contributors to MDS pathogenesis and which may be therapeutically and preventatively targeted.