Rhys G. Morgan
LEF-1 drives aberrant ?-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.
Kate J. Heesom
Marieangela C. Wilson
Andrew D. Davidson
Alexander Greenhough Alexander.Greenhough@uwe.ac.uk
Associate Professor of Biomedical Science
Ann C. Williams
Marian L. Waterman
Richard L. Darley
Canonical Wnt/?-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized ?-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia patients; however, some patients exhibit little or no nuclear ?-catenin even where cytosolic ?-catenin is abundant. Control of the subcellular localization of ?-catenin therefore represents an additional mechanism regulating Wnt signaling in hematopoietic cells. To investigate the factors mediating the nuclear-localization of ?-catenin we carried out the first nuclear/cytoplasmic proteomic analysis of the ?-catenin interactome in myeloid leukemia cells and identified putative novel ?-catenin interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear ?-catenin) versus Wnt-unresponsive cells (low nuclear ?-catenin) suggested the transcriptional partner, LEF-1, could direct the nuclear-localization of ?-catenin. The relative levels of nuclear LEF-1 and ?-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF-1 knockdown perturbed ?-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF-1 overexpression was able to promote both nuclear-localization and ?-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This is the first ?-catenin interactome study in hematopoietic cells and reveals LEF-1 as a mediator of nuclear ?-catenin level human myeloid leukemia.
Morgan, R. G., Ridsdale, J., Payne, M., Heesom, K. J., Wilson, M. C., Davidson, A. D., …Darley, R. L. (2019). LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells. Haematologica, 104(7), 1365-1377. https://doi.org/10.3324/haematol.2018.202846
|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 12, 2019|
|Publisher||Ferrata Storti Foundation|
|Peer Reviewed||Peer Reviewed|
|Keywords||acute myeloid leukemia, B-Catenin, LEF-1, Signal transduction, WNT signaling|
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