Rhys G. Morgan
LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells
Morgan, Rhys G.; Ridsdale, Jenna; Payne, Megan; Heesom, Kate J.; Wilson, Marieangela C.; Davidson, Andrew D.; Greenhough, Alexander; Davies, Sara; Williams, Ann C.; Blair, Allison; Waterman, Marian L.; Tonks, Alex; Darley, Richard L.
Authors
Jenna Ridsdale
Megan Payne
Kate J. Heesom
Marieangela C. Wilson
Andrew D. Davidson
Alexander Greenhough Alexander.Greenhough@uwe.ac.uk
Associate Professor of Health Diagnostics
Sara Davies
Ann C. Williams
Allison Blair
Marian L. Waterman
Alex Tonks
Richard L. Darley
Abstract
Canonical Wnt/β-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized β-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia patients; however, some patients exhibit little or no nuclear β-catenin even where cytosolic β-catenin is abundant. Control of the subcellular localization of β-catenin therefore represents an additional mechanism regulating Wnt signaling in hematopoietic cells. To investigate the factors mediating the nuclear-localization of β-catenin we carried out the first nuclear/cytoplasmic proteomic analysis of the β-catenin interactome in myeloid leukemia cells and identified putative novel β-catenin interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear β-catenin) versus Wnt-unresponsive cells (low nuclear β-catenin) suggested the transcriptional partner, LEF-1, could direct the nuclear-localization of β-catenin. The relative levels of nuclear LEF-1 and β-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF-1 knockdown perturbed β-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF-1 overexpression was able to promote both nuclear-localization and β-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This is the first β-catenin interactome study in hematopoietic cells and reveals LEF-1 as a mediator of nuclear β-catenin level human myeloid leukemia.
Journal Article Type | Article |
---|---|
Acceptance Date | Jan 3, 2019 |
Online Publication Date | Jan 10, 2019 |
Publication Date | Jun 30, 2019 |
Deposit Date | Feb 12, 2019 |
Publicly Available Date | Feb 18, 2019 |
Journal | Haematologica |
Print ISSN | 0390-6078 |
Electronic ISSN | 1592-8721 |
Publisher | Ferrata Storti Foundation |
Peer Reviewed | Peer Reviewed |
Volume | 104 |
Issue | 7 |
Pages | 1365-1377 |
DOI | https://doi.org/10.3324/haematol.2018.202846 |
Keywords | acute myeloid leukemia, B-Catenin, LEF-1, Signal transduction, WNT signaling |
Public URL | https://uwe-repository.worktribe.com/output/854218 |
Publisher URL | https://doi.org/10.3324/haematol.2018.202846 |
Contract Date | Feb 12, 2019 |
Files
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