Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9Research in the context
Li-shu Zhang,
Xunlei Kang,
Jianming Lu,
Yuannyu Zhang,
Xiaofeng Wu,
Guojin Wu,
Junke Zheng,
Rubina Tuladhar,
Heping Shi,
Qiaoling Wang,
Lorraine Morlock,
Huiyu Yao,
Lily Jun-shen Huang,
Pascal Maire,
James Kim,
Noelle Williams,
Jian Xu,
Chuo Chen,
Cheng Cheng Zhang,
Lawrence Lum
Affiliations
Li-shu Zhang
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Xunlei Kang
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jianming Lu
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Yuannyu Zhang
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Xiaofeng Wu
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Guojin Wu
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Junke Zheng
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Rubina Tuladhar
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Heping Shi
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Qiaoling Wang
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Lorraine Morlock
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Huiyu Yao
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Lily Jun-shen Huang
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Pascal Maire
Institut Cochin, Université Paris-Descartes, Centre National de la Recherche Scientifique (CNRS), UMR, 8104, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U1016, Paris, France
James Kim
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Noelle Williams
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Jian Xu
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Children's Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Chuo Chen
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Cheng Cheng Zhang
Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
Lawrence Lum
Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Corresponding author.
Background: Chromosomal translocation-induced expression of the chromatin modifying oncofusion protein MLL-AF9 promotes acute myelocytic leukemia (AML). Whereas WNT/β-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/β-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/β-catenin-dependent growth of LICs. Small molecules disrupting WNT/β-catenin signaling block Six1 expression thereby disrupting leukemia driven by MLL fusion proteins.
