Molecular Mechanisms of MDS pathogenesis with aging

MDS随衰老发病的分子机制

• 批准号: 10737177
• 负责人: STAVROULA KOUSTENI
• 金额: $ 50万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737177
• 关键词: AML/MDS; Abnormal Karyotype; Acute Myelocytic Leukemia; Affect; Age; Age Factors; Aging; Automobile Driving; Bone Marrow; CD34 gene; Cells; Chronic; Clinical; Clonal Evolution; Clonal Hematopoietic Stem Cell; Clonality; Cytogenetics; DNMT3a mutation; Development; Disease; Disease remission; Down-Regulation; Dysmyelopoietic Syndromes; Early identification; Event; Evolution; Family member; Future; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Genomics; Goals; Growth; Hematology; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Heterogeneity; Human; Impairment; Inflammation; Inflammatory; Lead; Leukemic Hematopoietic Stem Cell; Malignant - descriptor; Modeling; Molecular; Morphology; Mus; Mutate; Mutation; Myelogenous; Myeloproliferative disease; NUP98 gene; Nuclear; Nuclear Pore Complex Proteins; Osteoblasts; Pathogenesis; Pathway interactions; Patients; Population; Preleukemia; Recurrence; Risk; Role; Sampling; Signal Transduction; Somatic Mutation; Stress; Testing; Therapeutic; Translating; Transplantation; age related; aging population; beta catenin; cancer cell; cancer stem cell; clinically relevant; cohort; conventional therapy; curative treatments; cytopenia; driver mutation; effective therapy; epigenomics; human model; improved; induced pluripotent stem cell; insight; mouse model; permissiveness; prognostic; stem cells; therapeutic target; transcriptomics

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.

项目摘要/摘要 在过去的十年中，已经为了解的发展和复杂性做出了重大努力 骨髓增生性综合征（MDS），导致鉴定具有明确定义的经常突变基因 临床，预后和治疗意义。但是，这尚未有效地翻译 治疗。 MD可以是少数疾病引发细胞的人群 常规疗法。对调节这些疾病的分子途径的改进了解 引发干细胞对于未来治疗疗法的发展至关重要。几个因素收敛到 诱导恶性细胞的进化。使用3个MD的小鼠模型（β-catenin诱导的NUP98-HOXD13-- 诱导和PU.1URHETMSH2 - / - 诱导的M​​DS模型）和患者细胞（MDS和配对MDS 转换的AML）我们已经确定了与MD诱导高度相关的转录签名和 疾病转变。该签名包括核孔蛋白（NUPS）家族成员的表达降低 与MDS细胞相比，在AML中。与健康相比，MDS细胞中NUPS表达也被下调 人类的HSC，与DNMT3A突变相关，在与年龄有关的克隆中很突出 造血（ARCH），在AML病例中从先前的MDS转变。在鼠标和人类IPSC模型中 MDS，降低NUPS表达会影响MDS细胞向AML爆炸的转化。我们的目标 应用是为了全面研究NUP途径在MDS诱导中的作用 克隆造血和注射以及MDS干细胞动力学的衰老相关因素 确定其行动的驱动因素和机制。为了实现这一目标，我们将定义机制 NUPS下调会影响MDS中干细胞的疾病生长； 确定随着衰老和衰老的衰老，NUPS表达降低对MDS启动的需求 拱形和炎症压力的相关因素；并确定NUPS如何促进克隆异质性 通过定义与NUP相关的MDS进化的遗传，分子和转录机制 老化。这些研究将确定为MD的重要促进者的机制和分子 发病机理，可能是热和预防靶向的。