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Molecular Mechanisms of MDS pathogenesis with aging

MDS随衰老发病的分子机制

基本信息

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
项目类别：
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

项目摘要

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.

项目总结/文摘