The EMT modulator SNAI1 contributes to AML pathogenesis via its interaction with LSD1
Catherine Carmichael, Jueqiong Wang, Thao M. Nguyen, Oluseyi Kolawole, Aissa Benyoucef, Charlotte De Mazière, Anna R. Milne, Sona Samuel, Kevin R. Gillinder, Soroor Hediyeh-zadeh, Anh Vo, Yizhou Huang, Kathy Knezevic, William R. L. McInnes, Benjamin J. Shields, H. L. Mitchell, Matthew E. Ritchie, Tim Lammens, Béatrice Lintermans, Pieter Van Vlierberghe, Nicholas C. Wong, Katharina Haigh, Julie A.I. Thoms, Emma Toulmin, David J. Curtis, Ethan P. Oxley, Ross A. Dickins, Dominik Beck, Andrew C. Perkins, Matthew P. McCormack, Melissa J. Davis, Geert Berx, Johannes Zuber, John E. Pimanda, Benjamin T. Kile, Steven Goossens, Jody J. Haigh
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.