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

Author:

Carmichael Catherine L.1ORCID,Wang Jueqiong1,Nguyen Thao1,Kolawole Oluseyi1,Benyoucef Aissa23,De Mazière Charlotte14,Milne Anna R.1ORCID,Samuel Sona1,Gillinder Kevin1ORCID,Hediyeh-zadeh Soroor5ORCID,Vo Anh N. Q.1,Huang Yizhou67ORCID,Knezevic Kathy7ORCID,McInnes William R. L.1ORCID,Shields Benjamin J.1,Mitchell Helen1ORCID,Ritchie Matthew E.5ORCID,Lammens Tim89ORCID,Lintermans Beatrice910,Van Vlierberghe Pieter910ORCID,Wong Nicholas C.111ORCID,Haigh Katharina123,Thoms Julie A. I.12ORCID,Toulmin Emma1,Curtis David J.113ORCID,Oxley Ethan P.1,Dickins Ross A.1ORCID,Beck Dominik67,Perkins Andrew1ORCID,McCormack Matthew P.1ORCID,Davis Melissa J.51415ORCID,Berx Geert49ORCID,Zuber Johannes16,Pimanda John E.71217,Kile Benjamin T.18,Goossens Steven1491019ORCID,Haigh Jody J.123

Affiliation:

1. Australian Centre for Blood Diseases, Monash University, Melbourne, VIC, Australia;

2. Department of Pharmacology and Therapeutics, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada;

3. Research Institute in Oncology and Hematology, CancerCare Manitoba, Winnipeg, MB, Canada;

4. Department for Biomedical Molecular Biology, Ghent University, Ghent, Belgium;

5. Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia;

6. Centre for Health Technologies and School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW, Australia;

7. Lowy Cancer Research Centre and Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia;

8. Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium;

9. Cancer Research Institute Ghent, Ghent, Belgium;

10. Department of Biomolecular Medicine, Ghent University, Ghent, Belgium;

11. Monash Bioinformatics Platform, Monash University, Melbourne, VIC, Australia;

12. Lowy Cancer Research Centre and School of Medical Sciences, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia;

13. Department of Clinical Haematology, Alfred Health, Melbourne, Australia;

14. Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia;

15. Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, VIC, Australia;

16. Research Institute of Molecular Pathology, Vienna, Austria;

17. Department of Haematology, Prince of Wales Hospital, Randwick, NSW, Australia;

18. Department of Anatomy and Developmental Biology, Monash Biomedicine Discovery Institute, Monash University, Melbourne, VIC, Australia; and

19. Department of Diagnostic Sciences, Ghent University, Ghent, Belgium;

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference52 articles.

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