Dnmt3a-null hematopoietic progenitor stem cells expand after busulfan treatment

• Published in: Experimental hematology Vol. 91; pp. 39 - 45.e2
• Main Authors: Chen, Jichun, Matatall, Katie A., Feng, Xingmin, Hormaechea-Agulla, Daniel, Maharjan, Mukesh, Young, Neal, King, Katherine Y.
• Format: Journal Article
• Language: English
• Published: 20.09.2020
• ISSN: 0301-472X; 1873-2399
• DOI: 10.1016/j.exphem.2020.09.192

Mutations in the gene encoding DNA Methyltransferase 3A ( DNMT3A ) are the most common in c lonal hematopoiesis (CH), an age-related condition that was recently demonstrated to affect outcomes in patients undergoing hematopoietic stem cell transplant (HSCT). Recent studies showed patients with CH have worse prognoses after HSCT, suggesting stress imposed by HSCT preconditioning agents may impact hematopoietic stem cell (HSC) dynamics in transplant recipients. In this study, we used a competitive transplantation mouse model to investigate how treatment with common preconditioning agents 5-fluorouracil (5-FU) or busulfan (BU) affects the prevalence of Dnmt3a −/− HSCs and progenitor cells in competition with WT cells. We found that, though sufficient to deplete peripheral blood counts, 5-FU preconditioning did not significantly alter the frequency of Dnmt3a-null hematopoietic stem and progenitor cells (HSPCs) in mosaic mice. In contrast, mice treated with BU had a 7-fold decline in total bone marrow cells and an increase in Dnmt3a-null HSPCs that was detectable in PB. Indeed, even though all mosaic mice had starting engraftment of ~10–40%, 85–100% of HSPCs were Dnmt3a-null in four of seven mice following BU treatment, indicating these cells expand dramatically during recovery. Overall, these results suggest that different preconditioning regimens have different effects on the expansion of Dnmt3amutant cells in patients with pre-existing CH. Thus, the presence of CH-associated mutants should be evaluated prior to selecting pre-conditioning regimens for HSCT.