AHA Scientific Sessions 2026 Abstract · Nov 2, 2026
TET2-Mutant Clonal Hematopoiesis Accelerates Atherosclerosis by Cell-Autonomous and Bystander Foam Cell Formation
By Brzechffa C, Fleischman A
Introduction: Clonal hematopoiesis of indeterminate potential (CHIP), characterized by somatic mutations such as TET2 in hematopoietic stem cells, is associated with increased atherosclerosis. Loss-of-function mutations in TET2 promote clonal expansion and heightened inflammation, but the mechanisms by which TET2-deficient CHIP accelerates atherosclerosis remain incompletely understood. Because macrophage foam cell formation is a critical early step in atherogenesis, we investigated whether Tet2 -deficient CHIP enhances foam cell formation in both mutant and surrounding wild-type (WT) bystander macrophages. Methods: To evaluate if Tet2- deficient CHIP affects foam cell formation, we utilized a murine competitive bone marrow transplant in recipient pro-atherosclerotic Ldlr- /- mice, receiving either a mixture of 90% wild-type (WT) competitor marrow and 10% marrow from either Tet2-/- or Tet2+/+ donors, with each population distinguished by differential CD45 allelic markers. Mice were fed a low saturated or high saturated fat diet for 9 weeks. To assess cell-autonomous effects, WT and Tet2 -/- bone marrow-derived macrophages (BMDMs) were incubated with DiI-oxidized LDL (DiI-oxLDL) or oxLDL for Oil Red O staining. To assess bystander effects, WT macrophages were treated with conditioned media from WT or Tet2 -/- BMDMs or co-cultured with WT or Tet2 -/- BMDMs before oxLDL stimulation. Results: High saturated fat-fed mice receiving Tet2 -/- marrow exhibited increased aortic plaque burden (1.17х10 ⁵ μm ² vs 2.76х10 ⁵ μm ² , p<0.05) and increased necrotic core area (19,048μm ² vs 47,390μm ² , p<0.05). In vitro cell culture revealed Tet2 -/- BMDMs demonstrated greater DiI-oxLDL uptake than WT BMDMs (MFI 39,660 vs 52,488, p<0.05) and higher number of oil red o+ vesicles (10 vs 18, p<0.05), indicating enhanced foam cell formation. WT macrophages exposed to Tet2 -/- conditioned media exhibited increased DiI-oxLDL uptake compared with WT-conditioned media controls (MFI 49,303 vs 59,059, p<0.05). Similarly, co-culture with Tet2 -/- macrophages increased oxLDL uptake by WT macrophages (MFI 17,640 vs 24,676, p<0.05). Western blot analysis demonstrated increased expression of scavenger receptor CD36 in WT macrophages exposed to Tet2 -/- conditioned media. Consistent with these findings, high saturated fat-fed mice receiving Tet2 -/- marrow exhibited elevated CD36 expression and percentage of bystander CD45.2+ Ly6C high monocytes (MFI 3350 vs 5440, p<0.05; 39.8% vs 45.6%, p<0.05). Conclusions: Our study demonstrates Tet2 -deficient macrophages exhibit enhanced lipid uptake and induce a pro-foam-cell phenotype in neighboring WT macrophages, potentially through increased CD36 expression. These findings highlight a novel concept that TET2 CHIP enhances atherosclerosis not only by exacerbating inflammation but also by propagating atherogenic phenotypes beyond the mutant clone.