The DNA damage-independent ATM signalling maintains CBP/DOT1L axis in MLL rearranged acute myeloid leukaemia.
Oncogene
; 43(25): 1900-1916, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38671157
ABSTRACT
The long-term maintenance of leukaemia stem cells (LSCs) is responsible for the high degree of malignancy in MLL (mixed-lineage leukaemia) rearranged acute myeloid leukaemia (AML). The DNA damage response (DDR) and DOT1L/H3K79me pathways are required to maintain LSCs in MLLr-AML, but little is known about their interplay. This study revealed that the DDR enzyme ATM regulates the maintenance of LSCs in MLLr-AML with a sequential protein-posttranslational-modification manner via CBP-DOT1L. We identified the phosphorylation of CBP by ATM, which confers the stability of CBP by preventing its proteasomal degradation, and characterised the acetylation of DOT1L by CBP, which mediates the high level of H3K79me2 for the expression of leukaemia genes in MLLr-AML. In addition, we revealed that the regulation of CBP-DOT1L axis in MLLr-AML by ATM was independent of DNA damage activation. Our findings provide insight into the signalling pathways involoved in MLLr-AML and broaden the understanding of the role of DDR enzymes beyond processing DNA damage, as well as identigying them as potent cancer targets.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Dano ao DNA
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Leucemia Mieloide Aguda
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Transdução de Sinais
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Histona-Lisina N-Metiltransferase
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Proteína de Leucina Linfoide-Mieloide
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Proteínas Mutadas de Ataxia Telangiectasia
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article