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

• Published in: Blood Vol. 136; no. 8; pp. 957 - 973
• Main Authors: Carmichael, Catherine L., Wang, Jueqiong, Nguyen, Thao, Kolawole, Oluseyi, Benyoucef, Aissa, De Mazière, Charlotte, Milne, Anna R., Samuel, Sona, Gillinder, Kevin, Hediyeh-zadeh, Soroor, Vo, Anh N.Q., Huang, Yizhou, Knezevic, Kathy, McInnes, William R.L., Shields, Benjamin J., Mitchell, Helen, Ritchie, Matthew E., Lammens, Tim, Lintermans, Beatrice, Van Vlierberghe, Pieter, Wong, Nicholas C., Haigh, Katharina, Thoms, Julie A.I., Toulmin, Emma, Curtis, David J., Oxley, Ethan P., Dickins, Ross A., Beck, Dominik, Perkins, Andrew, McCormack, Matthew P., Davis, Melissa J., Berx, Geert, Zuber, Johannes, Pimanda, John E., Kile, Benjamin T., Goossens, Steven, Haigh, Jody J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.08.2020; American Society of Hematology
• Subjects: Animals; Cell Line, Tumor; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Epithelial-Mesenchymal Transition - genetics; HEK293 Cells; Histone Demethylases - genetics; Histone Demethylases - metabolism; HL-60 Cells; Humans; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - metabolism; Leukemia, Myeloid, Acute - pathology; Mice; Mice, Transgenic; Myeloid Neoplasia; Protein Binding; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Snail Family Transcription Factors - physiology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2019002548

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. •KDM1A/LSD1 is a new therapeutic target for AML; we have identified SNAI1 as a pathological modulator of KDM1A/LSD1 target selection in AML.•Targeting the SNAI1-LSD1 complex or its downstream targets may be a novel and potent therapeutic strategy for the treatment of AML. [Display omitted]