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

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, Jun-Shen Huang, Pascal Maire, James Kim, Noelle S Williams, Jian Xu, Chuo Chen, Chengcheng Zhang, Lawrence Lum

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Abstract

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.

Original languageEnglish (US)
JournalEBioMedicine
DOIs
StateAccepted/In press - Jan 1 2018

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ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhang, L. S., Kang, X., Lu, J., Zhang, Y., Wu, X., Wu, G., Zheng, J., Tuladhar, R., Shi, H., Wang, Q., Morlock, L., Yao, H., Huang, J-S., Maire, P., Kim, J., Williams, N. S., Xu, J., Chen, C., Zhang, C., & Lum, L. (Accepted/In press). Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9. EBioMedicine. https://doi.org/10.1016/j.ebiom.2018.11.039