Demographic and CHIP-specific details for patients who donated peripheral blood samples.

Demographic and CHIP-specific details for patients who donated adipose tissue samples.

Single-cell RNA sequencing captures expected cell types in peripheral blood and adipose tissue.

a) UMAP of peripheral blood mononuclear cells (PBMCs) from patients with TET2 and DNMT3A CHIP and controls. b) UMAP of adipose tissue cells from patients with TET2 and DNMT3A CHIP and controls. Created with BioRender.com/t4etn0l.

CHIP affects monocyte movement through alterations to monocyte-endothelial cell interactions.

a) Barplot representing signaling strength between classical monocytes and endothelial cells for interactions related to transendothelial migration. Statistical significance evaluated with a Wilcoxon signed-rank test. * indicates p-value < 0.05. b) Schematic explaining in vitro model of monocyte movement over endothelial cells. c) Barplot showing normalized movement of monocytes with CHIP mutations and control monocytes over endothelial cells. Endothelial cells were cultured with dimethyl sulfoxide (DMSO) for 24 hours prior to co-culturing. Mean velocity for individual cells was normalized by dividing by the average velocity of control monocytes. Statistical significance was evaluated with a two-sample T test. * indicates p-value < 0.05. Created with BioRender.com/0mz24zc.

Single-cell foundation model nominates genetic perturbations capable of rescuing interactions between monocytes and endothelial cells in TET2 CHIP.

a) UMAP of RNA-based embeddings representing CD14+ monocytes from patients with TET2 CHIP and controls. b) UMAP of Geneformer embeddings after fine-tuning to separate CD14+ monocytes from patients with TET2 CHIP and controls. c) Upset plot highlighting overlap of perturbation candidates identified by CellChat and Geneformer. d) Violin plot showing expression of ITGB2 in CD14+ monocytes. Statistical significance evaluated with a Wald test in a negative binomial generalized linear model (GLM). * indicates adjusted p-value < 0.05. e) Violin plots showing expression of CXCL2 and CXCL3 in CD14+ monocytes.

ICAM and CXCR2 are effective targets for restoring movement of TET2-mutated monocytes over endothelial cells.

a) Barplot showing normalized mean velocity of TET2-mutated monocytes over endothelial cells that were cultured with DMSO or with SAR1118, an ICAM1 inhibitor, at 0.1nM, 1nM, and 2nM for 24 hours. Statistical significance evaluated with a two-sample T test. * indicates p-value < 0.05. b) Barplot showing normalized mean velocity of TET2-mutated monocytes over endothelial cells after monocytes were cultured for 24 hours with DMSO or AZD5069, a CXCR2 inhibitor, at 1uM, 2uM, 5uM, and 10uM.