Installation of a cancer promoting WNT/SIX1 signaling axis by the oncofusion protein MLL-AF9
| Autor: | Huiyu Yao, Junke Zheng, Li-shu Zhang, Lawrence G. Lum, Cheng Cheng Zhang, Lily Jun Shen Huang, Jianming Lu, Heping Shi, Noelle S. Williams, Pascal Maire, James Kim, Rubina Tuladhar, Lorraine Morlock, Chuo Chen, Xiaofeng Wu, Jian Xu, Xunlei Kang, Qiaoling Wang, Yuannyu Zhang, Guojin Wu |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Genetically modified mouse Research paper Oncogene Proteins Fusion THP-1 Cells HL-60 Cells Biology General Biochemistry Genetics and Molecular Biology Receptors G-Protein-Coupled Small Molecule Libraries Mice 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases Gene expression Animals Humans Wnt Signaling Pathway neoplasms Homeodomain Proteins Effector HEK 293 cells Intracellular Signaling Peptides and Proteins Wnt signaling pathway General Medicine Fusion protein 3. Good health Chromatin Cell biology Leukemia Myeloid Acute HEK293 Cells 030104 developmental biology 030220 oncology & carcinogenesis Neoplastic Stem Cells Transcription Factor 7-Like 2 Protein TCF7L2 Myeloid-Lymphoid Leukemia Protein Neoplasm Transplantation HeLa Cells |
| Zdroj: | EBioMedicine |
| ISSN: | 2352-3964 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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