The EMT Modulator SNAI1 Contributes to AML Pathogenesis via Its Interaction With LSD1

Catherine L. Carmichael, Jueqiong Wang, Thao Nguyen, Oluseyi Kolawole, Aissa Benyoucef, Charlotte De Mazière, Anna R. Milne, Sona Samuel, Kevin Gillinder, Soroor Hediyeh-Zadeh, Anh N Q Vo, Yizhou Huang, Kathy Knezevic, William R L McInnes, Benjamin J Shields, Helen Mitchell, Matthew E Ritchie, Tim Lammens, Beatrice Lintermans, Pieter Van VlierbergheNicholas C. Wong, Katharina Haigh, Julie A I Thoms, Emma Toulmin, David J. Curtis, Ethan P. Oxley, Ross A. Dickins, Dominik Beck, Andrew Perkins, Mathew P McCormack, Melissa J Davis, Geert Berx, Johannes Zuber, John E Pimanda, Benjamin T Kile, Steven Goossens, Jody J Haigh

Research output: Contribution to journalArticleResearchpeer-review

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.
Original languageEnglish
Pages (from-to)957-973
Number of pages17
JournalBlood
Volume136
Issue number8
DOIs
Publication statusPublished - 20 Aug 2020

Keywords

  • EMT
  • SNAI1 transcription factor
  • AML
  • LSD1
  • H3K4Me1/2 demethylation
  • myelopoiesis
  • self-renewal
  • transcriptional and chromatin profiling

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