Aberrant DNA methylation impacts HOX genes expression in bone marrow mesenchymal stromal cells of myelodysplastic syndromes and de novo acute myeloid leukemia.
Bone Marrow
/ pathology
Bone Marrow Cells
/ metabolism
CCAAT-Enhancer-Binding Proteins
/ genetics
DNA Methylation
Genes, Homeobox
/ genetics
Humans
Leukemia, Myeloid, Acute
/ pathology
Mesenchymal Stem Cells
/ metabolism
Myelodysplastic Syndromes
/ genetics
Transcription Factors
/ genetics
Ubiquitin-Protein Ligases
/ metabolism
Journal
Cancer gene therapy
ISSN: 1476-5500
Titre abrégé: Cancer Gene Ther
Pays: England
ID NLM: 9432230
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
received:
10
09
2021
accepted:
08
02
2022
revised:
12
12
2021
pubmed:
24
2
2022
medline:
25
8
2022
entrez:
23
2
2022
Statut:
ppublish
Résumé
DNA methylation, a major biological process regulating the transcription, contributes to the pathophysiology of hematologic malignancies, and hypomethylating agents are commonly used to treat myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML). In these diseases, bone marrow mesenchymal stromal cells (MSCs) play a key supportive role through the production of various signals and interactions. The DNA methylation status of MSCs, likely to reflect their functionality, might be relevant to understand their contribution to the pathophysiology of these diseases. Consequently, the aim of our study was to analyze the modifications of DNA methylation profiles of MSCs induced by MDS or AML. MSCs from MDS/AML patients were characterized via 5-methylcytosine quantification, gene expression profiles of key regulators of DNA methylation, identification of differentially methylated regions (DMRs) by methylome array, and quantification of DMR-coupled genes expression. MDS and AML-MSCs displayed global hypomethylation and under-expression of DNMT1 and UHRF1. Methylome analysis revealed aberrant methylation profiles in all MDS and in a subgroup of AML-MSCs. This aberrant methylation was preferentially found in the sequence of homeobox genes, especially from the HOX family (HOXA1, HOXA4, HOXA5, HOXA9, HOXA10, HOXA11, HOXB5, HOXC4, and HOXC6), and impacted on their expression. These results highlight modifications of DNA methylation in MDS/AML-MSCs, both at global and focal levels dysregulating the expression of HOX genes well known for their involvement in leukemogenesis. Such DNA methylation in MSCs could be the consequence of the malignant disease or could participate in its development through defective functionality or exosomal transfer of HOX transcription factors from MSCs to hematopoietic cells.
Identifiants
pubmed: 35194200
doi: 10.1038/s41417-022-00441-w
pii: 10.1038/s41417-022-00441-w
doi:
Substances chimiques
CCAAT-Enhancer-Binding Proteins
0
Transcription Factors
0
UHRF1 protein, human
EC 2.3.2.27
Ubiquitin-Protein Ligases
EC 2.3.2.27
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1263-1275Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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