Kdm6a deficiency restricted to mouse hematopoietic cells causes an age- and sex-dependent myelodysplastic syndrome-like phenotype.

Autor: Tian L; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, United States of America., Chavez M; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, United States of America., Chang GS; McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States of America., Helton NM; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, United States of America., Katerndahl CDS; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, United States of America., Miller CA; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, United States of America.; McDonnell Genome Institute, Washington University School of Medicine, St. Louis, MO, United States of America., Wartman LD; Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, St Louis, MO, United States of America.
Jazyk: angličtina
Zdroj: PloS one [PLoS One] 2021 Nov 15; Vol. 16 (11), pp. e0255706. Date of Electronic Publication: 2021 Nov 15 (Print Publication: 2021).
DOI: 10.1371/journal.pone.0255706
Abstrakt: Kdm6a/Utx, a gene on the X chromosome, encodes a histone H3K27me3 demethylase that has an orthologue on the Y chromosome (Uty) (Zheng et al. 2018). We previously identified inactivating mutations of Kdm6a in approximately 50% of mouse acute promyelocytic leukemia samples; however, somatic mutations of KDM6A are more rare in human AML samples, ranging in frequency from 2-15% in different series of patients, where their role in pathogenesis is not yet clear. In this study, we show that female Kdm6aflox/flox mice (with allele inactivation initiated by Vav1-Cre in hematopoietic stem and progenitor cells (HSPCs) have a sex-specific phenotype that emerges with aging, with features resembling a myelodysplastic syndrome (MDS). Female Kdm6a-knockout (KO) mice have an age-dependent expansion of their HSPCs with aberrant self-renewal, but they did not differentiate normally into downstream progeny. These mice became mildly anemic and thrombocytopenic, but did not develop overt leukemia, or die from these cytopenias. ChIP-seq and ATAC-seq studies showed only minor changes in H3K27me3, H3K27ac, H3K4me, H3K4me3 and chromatin accessibility between Kdm6a-WT and Kdm6a-KO mice. Utilizing scRNA-seq, Kdm6a loss was linked to the transcriptional repression of genes that mediate hematopoietic cell fate determination. These data demonstrate that Kdm6a plays an important role in normal hematopoiesis, and that its inactivation may contribute to AML pathogenesis.
Competing Interests: The authors have declared that no competing interests exist.
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje