Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9.
EBioMedicine
; 39: 145-158, 2019 Jan.
Article
em En
| MEDLINE
| ID: mdl-30528456
ABSTRACT
BACKGROUND:
Chromosomal translocation-induced expression of the chromatin modifying oncofusion protein MLL-AF9 promotes acute myelocytic leukemia (AML). Whereas WNT/ß-catenin signaling has previously been shown to support MLL-AF9-driven leukemogenesis, the mechanism underlying this relationship remains unclear.METHODS:
We used two novel small molecules targeting WNT signaling as well as a genetically modified mouse model that allow targeted deletion of the WNT protein chaperone Wntless (WLS) to evaluate the role of WNT signaling in AML progression. ATAC-seq and transcriptome profiling were deployed to understand the cellular consequences of disrupting a WNT signaling in leukemic initiating cells (LICs).FINDINGS:
We identified Six1 to be a WNT-controlled target gene in MLL-AF9-transformed leukemic initiating cells (LICs). MLL-AF9 alters the accessibility of Six1 DNA to the transcriptional effector TCF7L2, a transducer of WNT/ß-catenin gene expression changes. Disruption of WNT/SIX1 signaling using inhibitors of the Wnt signaling delays the development of AML.INTERPRETATION:
By rendering TCF/LEF-binding elements controlling Six1 accessible to TCF7L2, MLL-AF9 promotes WNT/ß-catenin-dependent growth of LICs. Small molecules disrupting WNT/ß-catenin signaling block Six1 expression thereby disrupting leukemia driven by MLL fusion proteins.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Leucemia Mieloide Aguda
/
Proteínas de Fusão Oncogênica
/
Proteínas de Homeodomínio
/
Proteína de Leucina Linfoide-Mieloide
/
Bibliotecas de Moléculas Pequenas
/
Via de Sinalização Wnt
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
Idioma:
En
Revista:
EBioMedicine
Ano de publicação:
2019
Tipo de documento:
Article
País de afiliação:
Estados Unidos