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

doi:10.1016/j.ebiom.2018.11.039

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 journal › Article › peer-review

13 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 language	English (US)
Pages (from-to)	145-158
Number of pages	14
Journal	EBioMedicine
Volume	39
DOIs	https://doi.org/10.1016/j.ebiom.2018.11.039
State	Published - Jan 2019

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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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. (2019). Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9. EBioMedicine, 39, 145-158. https://doi.org/10.1016/j.ebiom.2018.11.039

Zhang, LS, 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, NS, Xu, J, Chen, C , Zhang, C & Lum, L 2019, 'Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9', EBioMedicine, vol. 39, pp. 145-158. https://doi.org/10.1016/j.ebiom.2018.11.039

@article{185b8c050de24db8b24201b232a5cc83,

title = "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/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.",

author = "Zhang, {Li shu} and Xunlei Kang and Jianming Lu and Yuannyu Zhang and Xiaofeng Wu and Guojin Wu and Junke Zheng and Rubina Tuladhar and Heping Shi and Qiaoling Wang and Lorraine Morlock and Huiyu Yao and Jun-Shen Huang and Pascal Maire and James Kim and Williams, {Noelle S} and Jian Xu and Chuo Chen and Chengcheng Zhang and Lawrence Lum",

note = "Publisher Copyright: {\textcopyright} 2018 The Authors",

year = "2019",

month = jan,

doi = "10.1016/j.ebiom.2018.11.039",

language = "English (US)",

volume = "39",

pages = "145--158",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier BV",

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T1 - Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9

AU - Zhang, Li shu

AU - Kang, Xunlei

AU - Lu, Jianming

AU - Zhang, Yuannyu

AU - Wu, Xiaofeng

AU - Wu, Guojin

AU - Zheng, Junke

AU - Tuladhar, Rubina

AU - Shi, Heping

AU - Wang, Qiaoling

AU - Morlock, Lorraine

AU - Yao, Huiyu

AU - Huang, Jun-Shen

AU - Maire, Pascal

AU - Kim, James

AU - Williams, Noelle S

AU - Xu, Jian

AU - Chen, Chuo

AU - Zhang, Chengcheng

AU - Lum, Lawrence

PY - 2019/1

Y1 - 2019/1

N2 - 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.

AB - 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.

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DO - 10.1016/j.ebiom.2018.11.039

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SN - 2352-3964

VL - 39

SP - 145

EP - 158

JO - EBioMedicine

JF - EBioMedicine

ER -

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

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