Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogen [scRNA-Seq]

Blood cancers are generally more common in males, and the prevalence of most mutations that drive clonal hematopoiesis and myeloid malignancies is higher in males. In contrast, hematopoietic DNMT3A mutations are more common in females. We sought to investigate if sex hormones might contribute to the female predominance of DNMT3A mutations. We used single-cell RNA- and ATAC-sequencing in murine models to examine genotype-specific sex differences and sex hormone effects on hematopoietic stem and progenitor cells. Single-cell RNA-sequencing was performed of hematopoietic stem and progenitor (Lineage- Sca-1+ c-kit+ [LSK]) cells from unmanipulated male and female mice with wild-type (WT) or Dnmt3a-mutant backgrounds, and from ovariectomized mice transplanted with WT or Dnmt3a-mutant bone marrow cells and treated with a single dose of estradiol, dihydrotestosterone (DHT), or vehicle. Single-cell ATAC-sequencing was performed of LSK cells from unmanipulated female WT or Dnmt3a-mutant mice.