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

Research output: Contribution to journalArticle

5 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    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