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, Greenhough, Alexander, Davies, Sara, Williams, Ann C, Blair, Allison, Waterman, Marian L, Tonks, Alex and Darley, Richard L (2019) LEF-1 drives aberrant β-catenin nuclear localization in myeloid leukemia cells. Haematologica, 104 (7). pp. 1365-1377. ISSN 1592-8721

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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.

Item Type: Article
Keywords: β-Catenin; Wnt Signaling; LEF-1; Myeloid; Leukemia; Interactome
Schools and Departments: School of Life Sciences > Biochemistry
Research Centres and Groups: Haematology Research Group
Depositing User: Rhys Morgan
Date Deposited: 09 Jan 2019 14:13
Last Modified: 22 Aug 2019 14:00
URI: http://sro.sussex.ac.uk/id/eprint/81128

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Project NameSussex Project NumberFunderFunder Ref
Targeting nuclear localisation of B-catenin in acute leukaemiaG2445The Kay Kendall Leukaemia Fund (KKLF)KKL1051