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.

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