Dnmt3a Mutant Hematopoietic Stem Cells Produce Hyperactive T Cells with Increased Alloimmune and Anti-Leukemic Activity

Clonal hematopoiesis (CH) is the expansion of a hematopoietic stem cell (HSC) clone with an acquired leukemogenic mutation in individuals without any evident hematological abnormalities. CH is an age-related phenomenon associated with an increased risk of death from cardiovascular disease or hematol...

Full description

Saved in:
Bibliographic Details
Published in:Blood 2024-11, Vol.144, p.1288-1288
Main Authors: Wallace, LaShanale, Engelken, Mark, Myers, Jacquelyn A., Harper, John, Clark, Brandi, Cullins, David, Zoine, Jaquelyn T., Shanmugam, Raghuvaran, Schattgen, Stefan, Velasquez, M. Paulina, Sheppard, Heather, Crawford, Jeremy Chase, Thomas, Paul G., Obeng, Esther A.
Format: Article
Language:English
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Clonal hematopoiesis (CH) is the expansion of a hematopoietic stem cell (HSC) clone with an acquired leukemogenic mutation in individuals without any evident hematological abnormalities. CH is an age-related phenomenon associated with an increased risk of death from cardiovascular disease or hematologic malignancies. Epigenetic regulators account for ~80% of the genes mutated in CH, with DNA Methyltransferase 3a (DNMT3A) mutation being the most common. Recent clinical studies have found that, after allogenic stem cell transplantation, CH clones are highly transmitted from donor to recipient. DNMT3A mutations remain the most prevalent and patients with donor-derived CH have an increased risk of acute (Oran et. al. Leukemia 2021) or chronic (Frick et. al. JCO 2018) graft vs host disease (GVHD). A larger study found that recipients of DNMT3A-mutant donor-derived CH had a decreased leukemia relapse risk (Gibson et. al. JCO 2022). These results suggest that DNMT3A-mutant CHIP recipients have hyperactive T cells that may play a role in initiating GVHD or graft vs leukemia effect, but it has not been proven. To examine whether mutations in DNMT3A affect T cell function leading to GVHD and anti-leukemic effects, we used a murine Dnmt3aR878H/+ model harboring the clinically equivalent point mutation most seen in hematological malignancies (R882H, Loberg et. al. Leukemia 2019). We found that up to 80% of Dnmt3aR878H/+ mice developed a severe ulcerative dermatitis characterized by a hyperplastic epidermis with increased lymphocytic infiltration (p
ISSN:0006-4971
DOI:10.1182/blood-2024-208666