Inflammatory Stress Promotes Clonal Expansion of DNMT3A-mutant HSCs

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Principal Investigator: Grant Anthony Challen
Organization: WASHINGTON UNIVERSITY
Fiscal Year: 2024
Award: $422,691
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases

ABSTRACT
 Blood diseases such as myelodysplastic syndromes (MDS) arise from hematopoietic stem cells (HSCs)
that acquire genetic mutations which corrupt critical HSC functions. One of the most recurrently mutated
genes in these neoplasms is the de novo DNA methyltransferase enzyme DNMT3A. However, DNMT3A
mutations can occur in HSCs long before clinical presentation. Recent studies have shown that the HSC
clones that predominate with age often contain mutations that are characteristic of myeloid neoplasms. This
phenomenon is known as clonal hematopoiesis (CH), but only a small fraction of individuals with CH go on to
develop a blood disease. This suggests that in addition to genetics, there must be other factors which act
differently between individuals that select for propagation of HSCs with these mutations. Our lab is interested
in identifying factors that change with age which may provide selective pressures for these mutant clones,
focusing on inflammation. The prior funding period identified interferon gamma (IFNg) as an environmental
stressor that selects for the outgrowth of Dnmt3a-mutant HSCs. While chronic IFNg signaling is detrimental to
normal HSCs, functionality of Dnmt3a-mutant HSCs is preserved in this setting, presenting a mechanism
whereby HSCs with these mutations gain clonal dominance in settings of inflammation. New data generated in
our lab show that Dnmt3a-mutant HSCs are not only resistant to the detrimental effects of IFNg in vivo, but
also the mutant clones produce more IFNg themselves in response to inflammation. This is associated with
increased Cxcl9 expression from the mutant clones and T-cell infiltration into the BM. These observations form
the scientific premise for this renewal application. We hypothesize that IFNg production by Dnmt3a-mutant
clones suppresses other HSC genotypes and remodels the niche through T-cell infiltration to further reinforce
their competitive advantage. We propose the following Specific Aims to investigate these questions;
  Determine if IFNg production from Dnmt3a-mutant clones exacerbates their competitive
advantage.
  Determine if Dnmt3a-mutant clones remodel the BM niche.
  Examine the cellular and molecular mechanisms by which Dnmt3a-mutant cells are
 hypersensitive to IFNg.
 The overall goal of this work is to determine the mechanisms by which inflammatory signals promote clonal
expansion of Dnmt3a-mutant HSCs in the bone marrow. Approaches to eliminate or selectively inhibit
emerging DNMT3A-mutant HSC clones from high-risk CH+ individuals may provide a window for intervention
before the mutant cells are able to establish clonal dominance and evolve to fulminant disease.

Terms: <65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><Age><Aged 65 and Over><Allele Frequency><Assay><Autoimmune Diseases><Automobile Driving><Bioassay><Biological Assay><Blood><Blood Diseases><Blood Precursor Cell><Blood Reticuloendothelial System><Blood Serum><Bone Marrow><Bone Marrow Reticuloendothelial System><Bone Regeneration><Bone remodeling><Cancers><Candidate Disease Gene><Candidate Gene><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell division><Cells><Characteristics><Chronic><Clinical><Clonal Expansion><Clonal Hematopoietic Stem Cell><Collaborations><DNA Alteration><DNA Methyltransferase><DNA Modification Methylases><DNA Modification Methyltransferases><DNA Sequence Alteration><DNA methyltransferase 3 alpha mutation><DNA mutation><DNA-Methyltransferases><DNMT3a><DNMT3a mutation><Data><Development><Disease><Disease Progression><Disorder><Dnmt><Dysmyelopoietic Syndromes><Elderly><Environment><Enzyme Gene><Enzymes><Funding><Future><Gene Frequency><Gene variant><Generalized Growth><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Genomics><Genotype><Goals><Growth><HSC regeneration><HSC self-renewal><Hematologic Body System><Hematologic Diseases><Hematologic Organ System><Hematological Disease><Hematological Disorder><Hematopoiesis><Hematopoietic Body System><Hematopoietic Cell Tumor><Hematopoietic Cellular Control Mechanisms><Hematopoietic Malignancies><Hematopoietic Neoplasms><Hematopoietic Neoplasms including Lymphomas><Hematopoietic Progenitor Cells><Hematopoietic System><Hematopoietic Tumor><Hematopoietic and Lymphoid Cell Neoplasm><Hematopoietic and Lymphoid Neoplasms><Hematopoietic stem cells><High Prevalence><Human><IFN-Gamma><IFN-g><IFN-γ><IFNG><IFNγ><Immune Interferon><Individual><Infection><Inflammation><Inflammatory><Interferon Gamma><Interferon Type II><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Life><Malignant Hematopoietic Neoplasm><Malignant Neoplasms><Malignant Tumor><Modeling><Modern Man><Modification Methylases><Molecular><Mutant Strains Mice><Mutate><Mutation><Myelodysplastic Disease><Myelodysplastic Syndromes><Myeloid Disease><Myeloid Malignancy><Myeloid Neoplasm><Myeloid Tumor><Myeloproliferative Disorders><Myeloproliferative Tumors><Myeloproliferative disease><Neoplasms><Pathway interactions><Patients><Persons><Process><Production><Publishing><Recurrence><Recurrent><Refractory Anemia with an Excess of Blasts><Refractory anaemia with excess blasts><Research Resources><Resistance><Resources><Risk><Role><Sequence Alteration><Serum><Signal Transduction><Signal Transduction Systems><Signaling><Site-Specific DNA-methyltransferase><Smoldering Leukemia><Stress><Symptoms><System><T cell infiltration><T-Cells><T-Lymphocyte><Testing><Time><Tissue Growth><Ulcerated Colitis><Ulcerative Colitis><Up-Regulation><Upregulation><Variant><Variation><Work><above age 65><adult progenitor><adult stem cell><advanced age><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age associated alterations><age associated changes><age correlated alterations><age correlated changes><age dependent alterations><age dependent changes><age of 65 years onward><age related alterations><age related changes><age specific alterations><age specific changes><aged 65 and greater><aged 65+><aged ≥65><ages><allele variant><allelic frequency><allelic variant><alterations with age><autoimmune condition><autoimmune disorder><autoimmunity disease><biological signal transduction><blood cancer><blood cell formation><blood cell progenitor><blood disorder><blood progenitor><blood stem cell><blood stem cell self-renewal><blood-forming stem cell><bone remodelling><cancer of blood><cancer of the blood><cancer prevention><changes with age><clone hematopoietic stem cell><cohort><conditioning><cytokine><develop therapy><developmental><driver lesion><driver mutation><driving><environmental stresses><environmental stressor><experiment><experimental research><experimental study><experiments><fitness><genetic variant><genome mutation><genomic alteration><genomic variant><geriatric><hDNA methyltransferase 3a><hematopoietic progenitor><hematopoietic progenitor cell self-renewal><hematopoietic stem cell regeneration><hematopoietic stem cell self-renewal><hematopoietic stem progenitor cell><hemopoietic progenitor><hemopoietic stem cell><high risk><high risk group><high risk individual><high risk people><high risk population><human old age (65+)><in vivo><interest><intervention development><interventional strategy><lFN-Gamma><malignancy><microbial><mouse model><mouse mutant><murine model><mutant><myelodysplasia><myeloproliferative neoplasm><neoplasia><neoplasm/cancer><neoplastic growth><novel><old age><ontogeny><over 65 years><pathway><pharmacologic><preservation><pressure><prevent><preventing><progenitor cell function><progenitor function><recruit><regenerate bone><resistant><response><risk mitigation><senior citizen><social role><somatic progenitor><somatic stem cell><stem and progenitor cell function><stem and progenitor function><stem cell depletion><stem cell exhaustion><stem cell fatigue><stem cell function><therapy development><thymus derived lymphocyte><tool><treatment development><virtual><≥65 years>