Multiomic Profiling of Human Clonal Hematopoiesis Reveals Genotype and Cell-Specific Inflammatory Pathway Activation
Jonathan Brett Heimlich, Pawan Bhat, Alyssa Parker, Matthew T Jenkins, Caitlyn Vlasschaert, Jessica Ulloa, Joseph Van Amburg, Chad R Potts, Sydney Olson, Alexander J Silver, Ayesha Ahmad, Brian Sharber, Donovan Brown, Ningning Hu, Peter van Galen, Michael R. Savona, Alexander G. Bick, Paul Brent Ferrell, Jr.
Abstract
Clonal hematopoiesis (CH) is an age-associated phenomenon that increases risk for hematologic malignancy and cardiovascular disease. CH is thought to enhance disease risk through inflammation in the peripheral blood1. Here, we profile peripheral blood gene expression in 66,968 single cells from a cohort of 17 CH patients and 7 controls. Using a novel mitochondrial DNA barcoding approach, we were able to identify and separately compare mutant TET2 and DNMT3A cells to non-mutant counterparts. We discovered the vast majority of mutated cells were in the myeloid compartment. Additionally, patients harboring DNMT3A and TET2 CH mutations possessed a pro-inflammatory profile in CD14+ monocytes through previously unrecognized pathways such as galectin and macrophage Inhibitory Factor (MIF). We also found that T cells from CH patients, though mostly un-mutated, had decreased expression of GTPase of the immunity associated protein (GIMAP) genes, which are critical to T cell development, suggesting that CH impairs T cell function.
Datasets
1. Single Cell Sequencing of Human PBMCs in Clonal Hematopoeisis of Indeterminant Potential
Metadata
HTO_maxID
HTO_secondID
HTO_classification.global
sample
donor_id
CHIP
LANE
ProjectID
MUTATION
MUTATION.GROUP
sex_ontology_term_id
HTOID
scType_celltype
development_stage_ontology_term_id
cell_type_ontology_term_id
self_reported_ethnicity_ontology_term_id
assay_ontology_term_id
suspension_type
tissue_type
tissue_ontology_term_id
organism_ontology_term_id
disease_ontology_term_id
cell_type
assay
disease
organism
sex
tissue
self_reported_ethnicity
development_stage
DNMT3A Q816X (8%)4395 cells SRSF2 P95R (40%), TET2 L957Ifs*15 (51%)4379 cells TET2 R1516X (30%), TET2 Q659X (29%), SRSF2 P95H (3%)4367 cells SRSF2 (33%), TET2 Y1245Lfs*22 (27%), TET2 Q742X(42%)2895 cells DNMT3A W305X (24%)2486 cells DNMT3A R882H (13%)2383 cells DNMT3A splice (7%)2314 cells TET2 V1900F (2%)2082 cells DNMT3A R882H (20%), IDH2 R140Q (10%), TP53 R273C (5%)1901 cells DNMT3A M880V (5%)1748 cells DNMT3A R729W (4%), DNMT3A R736C (2%)1731 cells DNMT3A R749C (9.1%)1354 cells TET2 C1378Y (23%)1122 cells Classical Monocytes18611 cells Naive CD4+ T cells18470 cells Natural killer cells9014 cells CD8+ NKT-like cells8273 cells Naive CD8+ T cells2673 cells ISG expressing immune cells2295 cells Effector CD8+ T cells1284 cells Non-classical monocytes920 cells Erythroid-like and erythroid precursor cells435 cells Effector CD4+ T cells382 cells Plasmacytoid Dendritic cells197 cells Memory CD4+ T cells194 cells Myeloid Dendritic cells192 cells HANCESTRO:000556141 cells UBERON:000017866985 cells NCBITaxon:960666985 cells CD4-positive, alpha-beta T cell19046 cells CD14-positive monocyte18611 cells CD8-positive, alpha-beta T cell14525 cells natural killer cell9014 cells CD16-positive, CD56-dim natural killer cell, human920 cells erythroid lineage cell435 cells premalignant hematological system disease47354 cells Hispanic or Latin American4395 cells 61-year-old human stage7724 cells 71-year-old human stage4741 cells 81-year-old human stage4560 cells 39-year-old human stage4395 cells 74-year-old human stage4379 cells 85-year-old human stage4367 cells 78-year-old human stage4000 cells 73-year-old human stage3358 cells 70-year-old human stage3136 cells 83-year-old human stage2967 cells 77-year-old human stage2895 cells 80-year-old human stage2486 cells 67-year-old human stage2383 cells 60-year-old human stage2340 cells 91-year-old human stage2314 cells 48-year-old human stage2134 cells 58-year-old human stage2082 cells 65-year-old human stage1901 cells 89-year-old human stage1738 cells 68-year-old human stage1731 cells 50-year-old human stage1354 cells Analyze this study
Source data
https://cellxgene.cziscience.com/collections/0aab20b3-c30c-4606-bd2e-d20dae739c45
Alias names
PMID38507736
Cite this study
Heimlich, J.B., Bhat, P., Parker, A.C., Jenkins, M.T., Vlasschaert, C., Ulloa, J., Van Amburg, J.C., Potts, C.R., Olson, S., Silver, A.J. and Ahmad, A., 2024. Multiomic Profiling of Human Clonal Hematopoiesis Reveals Genotype and Cell-Specific Inflammatory Pathway Activation. Blood Advances. https://doi.org/10.1182/bloodadvances.2023011445
