3194 – CLONAL HEMATOPOIESIS-ASSOCIATED DNMT3A MUTATIONS CAUSE INCREASED T CELL ACTIVATION AND DECREASED LEUKEMIC TUMOR BURDEN

• Published in: Experimental hematology 2024-08, Vol.137, p.104514, Article 104514
• Main Authors: Wallace, LaShanale, Engelken, Mark, Metidji, Amina, Myers, Jacquelyn, Sheppard, Heather, Crawford, Jeremy, Harper, John, Cullins, David, Thomas, Paul, Obeng, Esther
• Format: Article
• Language: English
• ISSN: 0301-472X
• DOI: 10.1016/j.exphem.2024.104514

Clonal hematopoiesis of indeterminate potential (CHIP) is the expansion of a hematopoietic stem cell (HSC) clone with an acquired leukemia-associated mutation in Healthy adults. CHIP is associated with an increased risk of death from leukemia or cardiovascular disease. Recent sequencing studies have shown that DNA Methyltransferase 3 Alpha (DNMT3A) mutations are frequently found in CHIP and are highly transmitted from donor to recipient after allogenic transplantation. Donor derived DNMT3A mutant CHIP is associated with increased graft vs host disease (GVHD) in all cases and improved progression free survival in some reports. To examine whether mutant DNMT3A affects T-cell function leading to GVHD and anti-leukemic effects, we used a murine Dnmt3aR878H/+ model harboring the clinically equivalent point mutation most commonly seen in CHIP (R882). We found an increased incidence of severe ulcerative dermatitis (80%) in Dnmt3aR878H/+ mice associated with an αβ T-cell infiltrate. Although the frequency of T-cells in spleen and thymus was similar between wildtype (WT) and Dnmt3aR878H/+ mice, the percentage of activated T-cells was significantly increased in mutant mice (p