Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9.

ABSTRACT:

Background

Chromosomal translocation-induced expression of the chromatin modifying oncofusion protein MLL-AF9 promotes acute myelocytic leukemia (AML). Whereas WNT/?-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/?-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/?-catenin-dependent growth of LICs. Small molecules disrupting WNT/?-catenin signaling block Six1 expression thereby disrupting leukemia driven by MLL fusion proteins.

SUBMITTER: Zhang LS 

PROVIDER: S-EPMC6354558 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature