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The EMT modulator SNAI1 contributes to AML pathogenesis via its interaction with LSD1.

Authors
  • Carmichael, Catherine L1
  • Wang, Jueqiong1
  • Nguyen, Thao1
  • Kolawole, Oluseyi1
  • Benyoucef, Aissa2, 3
  • De Mazière, Charlotte1, 4
  • Milne, Anna R1
  • Samuel, Sona1
  • Gillinder, Kevin1
  • Hediyeh-Zadeh, Soroor5
  • Vo, Anh N Q1
  • Huang, Yizhou6, 7
  • Knezevic, Kathy7
  • McInnes, William R L1
  • Shields, Benjamin J1
  • Mitchell, Helen1
  • Ritchie, Matthew E5
  • Lammens, Tim8, 9
  • Lintermans, Beatrice9, 10
  • Van Vlierberghe, Pieter9, 10
  • And 17 more
  • 1 Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia. , (Australia)
  • 2 Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. , (Canada)
  • 3 Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada. , (Canada)
  • 4 Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium. , (Belgium)
  • 5 Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. , (Australia)
  • 6 Centre for Health Technologies and School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia. , (Australia)
  • 7 Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. , (Australia)
  • 8 Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium. , (Belgium)
  • 9 Cancer Research Institute Ghent, Ghent, Belgium. , (Belgium)
  • 10 Department of Biomolecular Medicine, Ghent University, Ghent, Belgium. , (Belgium)
  • 11 Monash Bioinformatics Platform, Monash University, Melbourne, VIC, Australia. , (Australia)
  • 12 Lowy Cancer Research Centre and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia. , (Australia)
  • 13 Department of Clinical Haematology, Alfred Health, Melbourne, Australia. , (Australia)
  • 14 Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia. , (Australia)
  • 15 Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia. , (Australia)
  • 16 Research Institute of Molecular Pathology, Vienna, Austria. , (Austria)
  • 17 Department of Haematology, Prince of Wales Hospital, Randwick, NSW, Australia. , (Australia)
  • 18 Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia; and. , (Australia)
  • 19 Department of Diagnostic Sciences, Ghent University, Ghent, Belgium. , (Belgium)
Type
Published Article
Journal
Blood
Publisher
American Society of Hematology
Publication Date
Aug 20, 2020
Volume
136
Issue
8
Pages
957–973
Identifiers
DOI: 10.1182/blood.2019002548
PMID: 32369597
Source
Medline
Language
English
License
Unknown

Abstract

Modulators of epithelial-to-mesenchymal transition (EMT) have recently emerged as novel players in the field of leukemia biology. The mechanisms by which EMT modulators contribute to leukemia pathogenesis, however, remain to be elucidated. Here we show that overexpression of SNAI1, a key modulator of EMT, is a pathologically relevant event in human acute myeloid leukemia (AML) that contributes to impaired differentiation, enhanced self-renewal, and proliferation of immature myeloid cells. We demonstrate that ectopic expression of Snai1 in hematopoietic cells predisposes mice to AML development. This effect is mediated by interaction with the histone demethylase KDM1A/LSD1. Our data shed new light on the role of SNAI1 in leukemia development and identify a novel mechanism of LSD1 corruption in cancer. This is particularly pertinent given the current interest surrounding the use of LSD1 inhibitors in the treatment of multiple different malignancies, including AML. © 2020 by The American Society of Hematology.

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