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

1 Citation (Scopus)

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

Fingerprint

Catenins
Acute Myeloid Leukemia
Neoplasms
Proteins
Genetic Translocation
Gene Expression Profiling
Transducers
Chromatin
Leukemia
Molecules
Gene Expression
DNA
Gene expression
Growth
Genes
Fusion reactions

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9. / Zhang, Li shu; Kang, Xunlei; Lu, Jianming; Zhang, Yuannyu; Wu, Xiaofeng; Wu, Guojin; Zheng, Junke; Tuladhar, Rubina; Shi, Heping; Wang, Qiaoling; Morlock, Lorraine; Yao, Huiyu; Huang, Jun-Shen; Maire, Pascal; Kim, James; Williams, Noelle S; Xu, Jian; Chen, Chuo; Zhang, Chengcheng; Lum, Lawrence.

In: EBioMedicine, 01.01.2018.

Research output: Contribution to journalArticle

Zhang, Li shu ; Kang, Xunlei ; Lu, Jianming ; Zhang, Yuannyu ; Wu, Xiaofeng ; Wu, Guojin ; Zheng, Junke ; Tuladhar, Rubina ; Shi, Heping ; Wang, Qiaoling ; Morlock, Lorraine ; Yao, Huiyu ; Huang, Jun-Shen ; Maire, Pascal ; Kim, James ; Williams, Noelle S ; Xu, Jian ; Chen, Chuo ; Zhang, Chengcheng ; Lum, Lawrence. / Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9. In: EBioMedicine. 2018.
@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",
year = "2018",
month = "1",
day = "1",
doi = "10.1016/j.ebiom.2018.11.039",
language = "English (US)",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

TY - JOUR

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 - 2018/1/1

Y1 - 2018/1/1

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.

UR - http://www.scopus.com/inward/record.url?scp=85057616190&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85057616190&partnerID=8YFLogxK

U2 - 10.1016/j.ebiom.2018.11.039

DO - 10.1016/j.ebiom.2018.11.039

M3 - Article

C2 - 30528456

AN - SCOPUS:85057616190

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -