Epigenetic balance ensures mechanistic control of MLL amplification and rearrangement.
Cell
; 186(21): 4528-4545.e18, 2023 10 12.
Article
en En
| MEDLINE
| ID: mdl-37788669
ABSTRACT
MLL/KMT2A amplifications and translocations are prevalent in infant, adult, and therapy-induced leukemia. However, the molecular contributor(s) to these alterations are unclear. Here, we demonstrate that histone H3 lysine 9 mono- and di-methylation (H3K9me1/2) balance at the MLL/KMT2A locus regulates these amplifications and rearrangements. This balance is controlled by the crosstalk between lysine demethylase KDM3B and methyltransferase G9a/EHMT2. KDM3B depletion increases H3K9me1/2 levels and reduces CTCF occupancy at the MLL/KMT2A locus, in turn promoting amplification and rearrangements. Depleting CTCF is also sufficient to generate these focal alterations. Furthermore, the chemotherapy doxorubicin (Dox), which associates with therapy-induced leukemia and promotes MLL/KMT2A amplifications and rearrangements, suppresses KDM3B and CTCF protein levels. KDM3B and CTCF overexpression rescues Dox-induced MLL/KMT2A alterations. G9a inhibition in human cells or mice also suppresses MLL/KMT2A events accompanying Dox treatment. Therefore, MLL/KMT2A amplifications and rearrangements are controlled by epigenetic regulators that are tractable drug targets, which has clinical implications.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Epigénesis Genética
/
Proteína de la Leucemia Mieloide-Linfoide
Límite:
Adult
/
Animals
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Humans
/
Infant
Idioma:
En
Revista:
Cell
Año:
2023
Tipo del documento:
Article
País de afiliación:
Estados Unidos