Hematology Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
Section of Infectious Diseases, Department of Pediatrics, Stem Cells and Regenerative Medicine Center, Baylor College of Medicine, Houston, TX.
Exp Hematol. 2020 Nov;91:39-45.e2. doi: 10.1016/j.exphem.2020.09.192. Epub 2020 Sep 20.
Mutations in the gene encoding DNA methyltransferase 3A (DNMT3A) comprise the majority of mutations found in clonal hematopoiesis (CH), an age-related condition that was recently found to affect outcomes in patients undergoing hematopoietic stem cell transplant (HSCT). Recent studies have indicated that 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 the common preconditioning agents 5-fluorouracil (5-FU) and busulfan (BU) affect the prevalence of Dnmt3a HSCs and progenitor cells in competition with wild-type 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 sevenfold decline in total bone marrow cells and an increase in Dnmt3a-null HSPCs that was detectable in peripheral blood. Indeed, even though all mosaic mice had a starting engraftment of ∼10%-40%, 85%-100% of HSPCs were Dnmt3a-null in four of seven mice after BU treatment, indicating these cells expand dramatically during recovery. Overall, these results suggest that individual preconditioning regimens have different effects on the expansion of Dnmt3a-mutant cells in patients with pre-existing CH. Thus, the presence of CH-associated mutants should be evaluated prior to selecting preconditioning regimens for HSCT.
DNMT3A 基因编码突变构成克隆性造血 (CH) 中发现的大多数突变，CH 是一种与年龄相关的病症，最近发现它会影响接受造血干细胞移植 (HSCT) 的患者的结局。最近的研究表明，CH 患者在 HSCT 后预后更差，这表明 HSCT 预处理剂施加的压力可能会影响移植受者中的造血干细胞 (HSC) 动力学。在这项研究中，我们使用竞争移植小鼠模型来研究 5-氟尿嘧啶 (5-FU) 和白消安 (BU) 等常见预处理剂的治疗如何影响与野生型细胞竞争的 Dnmt3a HSCs 和祖细胞的流行率。我们发现，尽管足以耗尽外周血计数，但 5-FU 预处理不会显著改变嵌合小鼠中 Dnmt3a 缺失造血干细胞和祖细胞 (HSPC) 的频率。相比之下，用 BU 治疗的小鼠骨髓细胞总数下降了七倍，并且在外周血中可检测到 Dnmt3a 缺失的 HSPC 增加。事实上，即使所有嵌合小鼠的起始植入率约为 10%-40%，在接受 BU 治疗的七只小鼠中有四只的 HSPC 中 85%-100%为 Dnmt3a 缺失，表明这些细胞在恢复期间显著扩增。总体而言，这些结果表明，个体预处理方案对预先存在 CH 的患者中 Dnmt3a 突变细胞的扩增有不同的影响。因此，在为 HSCT 选择预处理方案之前，应评估 CH 相关突变体的存在。
