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.

项目概要/摘要 在过去的十年中，人们付出了巨大的努力来理解计算机科学的发展和复杂性。 骨髓增生异常综合征 (MDS)，导致识别出具有明确定义的反复突变基因 然而，这尚未转化为无效的。 MDS 可能由一小部分未通过治疗消除的疾病起始细胞引起。 更好地了解调节这些疾病的分子途径。 启动干细胞对于未来治疗疗法的发展至关重要。 使用 3 种 MDS 小鼠模型（β-连环蛋白诱导的、NUP98-HOXD13- 诱导恶性细胞的进化）。 诱导的和 PU.1UREhetMsh2–/– 诱导的 MDS 模型）和患者细胞（MDS 和配对的 MDS 转化的 AML）我们已经鉴定出与 MDS 诱导高度相关的转录特征， 该特征包括核孔蛋白 (NUP) 家族成员的表达减少。 在 AML 中，与健康细胞相比，MDS 细胞中的 NUP 表达也下调。 人类 HSC 与 DNMT3A 突变呈负相关，DNMT3A 突变在年龄相关克隆中很突出 造血 (ARCH)，在从以前的 MDS 转化而来的 AML 病例中，在小鼠和人类 iPSC 模型中。 MDS，减少 NUP 表达诱导 MDS 细胞转化为 AML 母细胞。 应用的目的是全面检查NUP通路在诱导MDS中的作用 克隆造血和炎症以及 MDS 干细胞动力学的衰老相关因素 确定他们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 中疾病起始干细胞的生长； 确定随衰老和衰老而导致 MDS 起始的 NUP 表达减少的要求 ARCH 和炎症应激的相关因素；并确定 NUP 如何促进克隆异质性 通过定义 NUP 相关 MDS 进化的遗传、分子和转录机制 这些研究将确定导致 MDS 的重要机制和分子。 发病机制，并可作为治疗和预防的目标。