Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogen
Summary: 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. Among ∼450,000 participants in the UK Biobank, the prev...
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Elsevier
2025-04-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124725002657 |
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| author | Julia Stomper Abhishek Niroula Roger Belizaire Marie McConkey Tagore Sanketh Bandaru Benjamin L. Ebert |
| author_facet | Julia Stomper Abhishek Niroula Roger Belizaire Marie McConkey Tagore Sanketh Bandaru Benjamin L. Ebert |
| author_sort | Julia Stomper |
| collection | DOAJ |
| description | Summary: 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. Among ∼450,000 participants in the UK Biobank, the prevalence of DNMT3A mutations and copy-number abnormalities is higher in females than males. In a murine model, Dnmt3a-mutant hematopoietic stem cells (HSCs) from unperturbed female mice had increased stemness gene expression compared to male and wild-type (WT) mice. Estrogen regulates HSCs, and we found that Dnmt3a mutations maintain stemness in the setting of estrogen-induced proliferative stress. Dnmt3a-mutant myeloid cells outcompeted WT cells under chronic estrogen treatment, an effect that was dependent on cell-intrinsic estrogen receptor alpha activity. Our studies indicate that estrogen might contribute to the female predominance of DNMT3A-mutant clonal hematopoiesis. |
| format | Article |
| id | doaj-art-b6bbe90d9d1b41a0b878abb6df418338 |
| institution | DOAJ |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-b6bbe90d9d1b41a0b878abb6df4183382025-08-20T03:16:46ZengElsevierCell Reports2211-12472025-04-0144411549410.1016/j.celrep.2025.115494Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogenJulia Stomper0Abhishek Niroula1Roger Belizaire2Marie McConkey3Tagore Sanketh Bandaru4Benjamin L. Ebert5Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USABroad Institute, Cambridge, MA 02142, USA; Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, 40530 Gothenburg, Sweden; SciLifeLab, University of Gothenburg, 40530 Gothenburg, SwedenDepartment of Pathology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Biochemistry and Cell Biology, Institute of Biomedicine, University of Gothenburg, 40530 Gothenburg, SwedenDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute, Cambridge, MA 02142, USA; Howard Hughes Medical Institute, Boston, MA 02215, USA; Corresponding authorSummary: 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. Among ∼450,000 participants in the UK Biobank, the prevalence of DNMT3A mutations and copy-number abnormalities is higher in females than males. In a murine model, Dnmt3a-mutant hematopoietic stem cells (HSCs) from unperturbed female mice had increased stemness gene expression compared to male and wild-type (WT) mice. Estrogen regulates HSCs, and we found that Dnmt3a mutations maintain stemness in the setting of estrogen-induced proliferative stress. Dnmt3a-mutant myeloid cells outcompeted WT cells under chronic estrogen treatment, an effect that was dependent on cell-intrinsic estrogen receptor alpha activity. Our studies indicate that estrogen might contribute to the female predominance of DNMT3A-mutant clonal hematopoiesis.http://www.sciencedirect.com/science/article/pii/S2211124725002657CP: Stem cell research |
| spellingShingle | Julia Stomper Abhishek Niroula Roger Belizaire Marie McConkey Tagore Sanketh Bandaru Benjamin L. Ebert Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogen Cell Reports CP: Stem cell research |
| title | Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogen |
| title_full | Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogen |
| title_fullStr | Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogen |
| title_full_unstemmed | Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogen |
| title_short | Sex differences in DNMT3A-mutant clonal hematopoiesis and the effects of estrogen |
| title_sort | sex differences in dnmt3a mutant clonal hematopoiesis and the effects of estrogen |
| topic | CP: Stem cell research |
| url | http://www.sciencedirect.com/science/article/pii/S2211124725002657 |
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