Document text
Principal Investigator: STAVROULA KOUSTENI
Organization: COLUMBIA UNIVERSITY HEALTH SCIENCES
Fiscal Year: 2024
Award: $500,000
Funding agency: National Institute on Aging
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.
Terms: <98 kD Nucleoporin><98-kD Gene Nucleoporin><ADIR2><AML - Acute Myeloid Leukemia><AML/MDS><Abnormal Karyotype><Acute Myeloblastic Leukemia><Acute Myelocytic Leukemia><Acute Myelogenous Leukemia><Affect><Age><Age Factors><Aging><Automobile Driving><Beta Cadherin-Associated Protein><Beta-1 Catenin><Blood Precursor Cell><Bone Marrow><Bone Marrow Reticuloendothelial System><CD34><CD34 gene><CUL-2><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Chronic><Clinical><Clonal Evolution><Clonal Hematopoietic Stem Cell><Clonality><Cytogenetics><DNA methyltransferase 3 alpha mutation><DNMT3a mutation><Development><Disease><Disease remission><Disorder><Down-Regulation><Dysmyelopoietic Syndromes><Early identification><Event><Evolution><Expression Signature><Family member><Future><GLFG-Repeat Containing Nucleoporin><Gene Expression Profile><Gene Transcription><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Genomics><Goals><Growth><HPCA1><Hematology><Hematopoiesis><Hematopoietic><Hematopoietic Cellular Control Mechanisms><Hematopoietic Progenitor Cells><Hematopoietic stem cells><Heterogeneity><Human><Impairment><Inflammation><Inflammatory><Intracellular Communication and Signaling><Lead><Leukemic Hematopoietic Stem Cell><Malignant><Malignant - descriptor><Malignant Cell><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Morphology><Murine><Mus><Mutate><Mutation><Myelodysplastic Disease><Myelodysplastic Syndromes><Myelogenous><Myeloid><Myeloid Disease><Myeloid Malignancy><Myeloid Neoplasm><Myeloid Tumor><Myeloproliferative Disorders><Myeloproliferative Tumors><Myeloproliferative disease><NUP196><NUP96 Gene><NUP98><NUP98 gene><NUP98-NUP96 Precursor><Nuclear><Nuclear Pore Complex Protein NUP98><Nuclear Pore Complex Proteins><Nucleoporin 98kD><Nucleoporin Gene><Nucleoporin NUP98><Nucleoporins><Nup Protein><Osteoblasts><PRO2286><Pathogenesis><Pathway interactions><Patients><Pb element><Population><Preleukemia><Progenitor Cells><RNA Expression><Recurrence><Recurrent><Refractory Anemia with an Excess of Blasts><Refractory anaemia with excess blasts><Remission><Risk><Role><Sampling><Signal Transduction><Signal Transduction Systems><Signaling><Smoldering Leukemia><Somatic Mutation><Stress><Testing><Therapeutic><Tissue Growth><Transcription><Translating><Transplantation><acute granulocytic leukemia><acute myeloid leukemia><acute myeloid leukemia/myelodysplastic syndrome><age associated><age correlated><age dependent><age linked><age related><age specific><aged group><aged groups><aged individual><aged individuals><aged people><aged person><aged persons><aged population><aged populations><ages><aging associated><aging population><aging related><beta catenin><biological signal transduction><blood cell formation><blood cell progenitor><blood progenitor><blood stem cell><blood-forming stem cell><cancer cell><cancer progenitor><cancer progenitor cells><cancer stem cell><clinical relevance><clinically relevant><clone hematopoietic stem cell><cohort><conventional therapy><conventional treatment><curative intervention><curative therapeutic><curative therapy><curative treatments><cytopenia><developmental><driver lesion><driver mutation><driving><effective therapy><effective treatment><epigenomics><gene expression pattern><gene expression signature><genome mutation><heavy metal Pb><heavy metal lead><hematopoietic progenitor><hematopoietic stem progenitor cell><hemopoietic><hemopoietic progenitor><hemopoietic stem cell><hiPSC><human iPS><human iPSC><human induced pluripotent cell><human induced pluripotent stem cells><human inducible stem cells><human model><iPS><iPSC><iPSCs><improved><induced human pluripotent stem cells><induced pluripotent cell><induced pluripotent stem cell><inducible pluripotent stem cell><insight><leukemic hematopoietic progenitor><leukemic hematopoietic stem and progenitor cells><malignant progenitor><malignant stem cell><model of human><mouse model><murine model><myelodysplasia><myeloproliferative neoplasm><nuclear pore complex protein 98><ontogeny><pathway><permissiveness><population aging><prognostic><social role><somatic variant><stem cells><therapeutic target><transcriptional profile><transcriptional signature><transcriptomics><transplant><β-catenin>