Peptidomimetic blockade of MYB in acute myeloid leukemia.
Nat Commun
; 9(1): 110, 2018 01 09.
Article
en En
| MEDLINE
| ID: mdl-29317678
ABSTRACT
Aberrant gene expression is a hallmark of acute leukemias. MYB-driven transcriptional coactivation with CREB-binding protein (CBP)/P300 is required for acute lymphoblastic and myeloid leukemias, including refractory MLL-rearranged leukemias. Using structure-guided molecular design, we developed a peptidomimetic inhibitor MYBMIM that interferes with the assembly of the molecular MYBCBP/P300 complex and rapidly accumulates in the nuclei of AML cells. Treatment of AML cells with MYBMIM led to the dissociation of the MYBCBP/P300 complex in cells, its displacement from oncogenic enhancers enriched for MYB binding sites, and downregulation of MYB-dependent gene expression, including of MYC and BCL2 oncogenes. AML cells underwent mitochondrial apoptosis in response to MYBMIM, which was partially rescued by ectopic expression of BCL2. MYBMIM impeded leukemia growth and extended survival of immunodeficient mice engrafted with primary patient-derived MLL-rearranged leukemia cells. These findings elucidate the dependence of human AML on aberrant transcriptional coactivation, and establish a pharmacologic approach for its therapeutic blockade.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Leucemia Mieloide Aguda
/
Activación Transcripcional
/
Proteínas Proto-Oncogénicas c-myb
/
Materiales Biomiméticos
/
Factores de Transcripción p300-CBP
/
Peptidomiméticos
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Nat Commun
Asunto de la revista:
BIOLOGIA
/
CIENCIA
Año:
2018
Tipo del documento:
Article
País de afiliación:
Estados Unidos