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

Background: Chromosomal translocation-induced expression of the chromatin modifying oncofusion protein MLL-AF9 promotes acute myelocytic leukemia (AML). Whereas WNT/D-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 Sixl to be a WNT-controlled target gene in MLL-AF9-transformed leukemic initiating cells (LICs).MLL-AF9 alters the accessibility of Sixl DNA to the transcriptional effector TCHL2, a transducer of WNT/Vicatenin gene expression changes. Disruption of Wf\ff/SIX1 signaling using inhibitors of the Wnt signaling delays the development of AML. interpretation: By rendering TCF/LEF-binding elements controlling Sixl accessible to TCF7L2, MLL-AF9 promotes WNE.'13-catenin-dependent growth of LlCs. Small molecules disrupting WNT,I3-catenin signaling block Sixl expression thereby disrupting leukemia driven by MLL fusion proteins. (C) 2018 The Authors. Published by Elsevier B.V.