Pharmacological targeting of the Wdr5-MLL interaction in C/EBPα N-terminal leukemia.
Nat Chem Biol
; 11(8): 571-578, 2015 Aug.
Article
en En
| MEDLINE
| ID: mdl-26167872
ABSTRACT
The CEBPA gene is mutated in 9% of patients with acute myeloid leukemia (AML). Selective expression of a short (30-kDa) CCAAT-enhancer binding protein-α (C/EBPα) translational isoform, termed p30, represents the most common type of CEBPA mutation in AML. The molecular mechanisms underlying p30-mediated transformation remain incompletely understood. We show that C/EBPα p30, but not the normal p42 isoform, preferentially interacts with Wdr5, a key component of SET/MLL (SET-domain/mixed-lineage leukemia) histone-methyltransferase complexes. Accordingly, p30-bound genomic regions were enriched for MLL-dependent H3K4me3 marks. The p30-dependent increase in self-renewal and inhibition of myeloid differentiation required Wdr5, as downregulation of the latter inhibited proliferation and restored differentiation in p30-dependent AML models. OICR-9429 is a new small-molecule antagonist of the Wdr5-MLL interaction. This compound selectively inhibited proliferation and induced differentiation in p30-expressing human AML cells. Our data reveal the mechanism of p30-dependent transformation and establish the essential p30 cofactor Wdr5 as a therapeutic target in CEBPA-mutant AML.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Compuestos de Bifenilo
/
Dihidropiridinas
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Leucemia Mieloide Aguda
/
Regulación Neoplásica de la Expresión Génica
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N-Metiltransferasa de Histona-Lisina
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Proteína de la Leucemia Mieloide-Linfoide
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Bibliotecas de Moléculas Pequeñas
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Antineoplásicos
Límite:
Animals
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Humans
Idioma:
En
Revista:
Nat Chem Biol
Asunto de la revista:
BIOLOGIA
/
QUIMICA
Año:
2015
Tipo del documento:
Article
País de afiliación:
Austria