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; Ngoc Vo; Yizhou Huang; Kathy Knezevic; William R L McInnes; Benjamin J Shields; Helen Mitchell; Matthew E Ritchie; Tim Lammens; Beatrice 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 Perkins; Mathew P McCormack; Melissa J Davis; Geert Berx; Johannes Zuber; John E Pimanda; Benjamin T Kile; Steven Goossens; Jody J Haigh

doi:10.1182/blood.2019002548

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, Ngoc 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 journal › Article › Research › peer-review

41 Citations (Scopus)

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 language	English
Pages (from-to)	957-973
Number of pages	17
Journal	Blood
Volume	136
Issue number	8
DOIs	https://doi.org/10.1182/blood.2019002548
Publication status	Published - 20 Aug 2020

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1182/blood.2019002548

314361647Final published version, 3.31 MB

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Carmichael, C. L., Wang, J., Nguyen, T., Kolawole, O., Benyoucef, A., De Mazière, C., Milne, A. R., Samuel, S., Gillinder, K., Hediyeh-Zadeh, S., Vo, N., Huang, Y., Knezevic, K., McInnes, W. R. L., Shields, B. J., Mitchell, H., Ritchie, M. E., Lammens, T., Lintermans, B., ... Haigh, J. J. (2020). The EMT Modulator SNAI1 Contributes to AML Pathogenesis via Its Interaction With LSD1. Blood, 136(8), 957-973. https://doi.org/10.1182/blood.2019002548

@article{2abd1b91db2d42f7ba0ae166cc326503,

title = "The EMT Modulator SNAI1 Contributes to AML Pathogenesis via Its Interaction With LSD1",

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.",

keywords = "EMT, SNAI1 transcription factor, AML, LSD1, H3K4Me1/2 demethylation, myelopoiesis, self-renewal, transcriptional and chromatin profiling",

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

year = "2020",

month = aug,

day = "20",

doi = "10.1182/blood.2019002548",

language = "English",

volume = "136",

pages = "957--973",

journal = "Blood",

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publisher = "American Society of Hematology",

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Carmichael, CL, Wang, J, Nguyen, T, Kolawole, O, Benyoucef, A, De Mazière, C, Milne, AR, Samuel, S, Gillinder, K, Hediyeh-Zadeh, S, Vo, N, Huang, Y, Knezevic, K, McInnes, WRL, Shields, BJ, Mitchell, H, Ritchie, ME, Lammens, T, Lintermans, B, Van Vlierberghe, P, Wong, NC, Haigh, K, Thoms, JAI, Toulmin, E, Curtis, DJ , Oxley, EP , Dickins, RA, Beck, D, Perkins, A , McCormack, MP, Davis, MJ, Berx, G, Zuber, J, Pimanda, JE, Kile, BT, Goossens, S & Haigh, JJ 2020, 'The EMT Modulator SNAI1 Contributes to AML Pathogenesis via Its Interaction With LSD1', Blood, vol. 136, no. 8, pp. 957-973. https://doi.org/10.1182/blood.2019002548

TY - JOUR

T1 - The EMT Modulator SNAI1 Contributes to AML Pathogenesis via Its Interaction With LSD1

AU - Carmichael, Catherine L.

AU - Wang, Jueqiong

AU - Nguyen, Thao

AU - Kolawole, Oluseyi

AU - Benyoucef, Aissa

AU - De Mazière, Charlotte

AU - Milne, Anna R.

AU - Samuel, Sona

AU - Gillinder, Kevin

AU - Hediyeh-Zadeh, Soroor

AU - Vo, Ngoc

AU - Huang, Yizhou

AU - Knezevic, Kathy

AU - McInnes, William R L

AU - Shields, Benjamin J

AU - Mitchell, Helen

AU - Ritchie, Matthew E

AU - Lammens, Tim

AU - Lintermans, Beatrice

AU - Van Vlierberghe, Pieter

AU - Wong, Nicholas C.

AU - Haigh, Katharina

AU - Thoms, Julie A I

AU - Toulmin, Emma

AU - Curtis, David J.

AU - Oxley, Ethan P.

AU - Dickins, Ross A.

AU - Beck, Dominik

AU - Perkins, Andrew

AU - McCormack, Mathew P

AU - Davis, Melissa J

AU - Berx, Geert

AU - Zuber, Johannes

AU - Pimanda, John E

AU - Kile, Benjamin T

AU - Goossens, Steven

AU - Haigh, Jody J

PY - 2020/8/20

Y1 - 2020/8/20

N2 - 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.

AB - 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.

KW - EMT

KW - SNAI1 transcription factor

KW - AML

KW - LSD1

KW - H3K4Me1/2 demethylation

KW - myelopoiesis

KW - self-renewal

KW - transcriptional and chromatin profiling

UR - https://pubmed.ncbi.nlm.nih.gov/32369597/

U2 - 10.1182/blood.2019002548

DO - 10.1182/blood.2019002548

M3 - Article

C2 - 32369597

SN - 0006-4971

VL - 136

SP - 957

EP - 973

JO - Blood

JF - Blood

IS - 8

ER -

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

Abstract

Keywords

UN SDGs

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Other files and links

Understanding the roles of the EMT transcription factors in epigenetic remodelling and myeloid cell transformation.

Cite this

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

Understanding the roles of the EMT transcription factors in epigenetic remodelling and myeloid cell transformation.

Cite this