Epigenetic regulator genes direct lineage switching in MLL/AF4 leukemia.
Journal
Blood
ISSN: 1528-0020
Titre abrégé: Blood
Pays: United States
ID NLM: 7603509
Informations de publication
Date de publication:
27 10 2022
27 10 2022
Historique:
accepted:
30
06
2022
received:
03
12
2021
pubmed:
16
7
2022
medline:
1
11
2022
entrez:
15
7
2022
Statut:
ppublish
Résumé
The fusion gene MLL/AF4 defines a high-risk subtype of pro-B acute lymphoblastic leukemia. Relapse can be associated with a lineage switch from acute lymphoblastic to acute myeloid leukemia, resulting in poor clinical outcomes caused by resistance to chemotherapies and immunotherapies. In this study, the myeloid relapses shared oncogene fusion breakpoints with their matched lymphoid presentations and originated from various differentiation stages from immature progenitors through to committed B-cell precursors. Lineage switching is linked to substantial changes in chromatin accessibility and rewiring of transcriptional programs, including alternative splicing. These findings indicate that the execution and maintenance of lymphoid lineage differentiation is impaired. The relapsed myeloid phenotype is recurrently associated with the altered expression, splicing, or mutation of chromatin modifiers, including CHD4 coding for the ATPase/helicase of the nucleosome remodelling and deacetylation complex. Perturbation of CHD4 alone or in combination with other mutated epigenetic modifiers induces myeloid gene expression in MLL/AF4+ cell models, indicating that lineage switching in MLL/AF4 leukemia is driven and maintained by disrupted epigenetic regulation.
Identifiants
pubmed: 35839448
pii: S0006-4971(22)00914-4
doi: 10.1182/blood.2021015036
pmc: PMC10488321
doi:
Substances chimiques
Myeloid-Lymphoid Leukemia Protein
149025-06-9
Oncogene Proteins, Fusion
0
Chromatin
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1875-1890Subventions
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/V001639/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/W01677X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S021590/1
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA215504
Pays : United States
Organisme : Cancer Research UK
ID : 12788
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0802259
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S021469/1
Pays : United Kingdom
Organisme : National Centre for the Replacement, Refinement and Reduction of Animals in Research
ID : NC/P002412/1
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
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