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LEF-1 drives aberrant ß-catenin nuclear localization in myeloid leukemia cells
Version 2 2023-06-12, 08:57
Version 1 2023-06-09, 16:25
journal contribution
posted on 2023-06-12, 08:57 authored by Rhys MorganRhys Morgan, Jenna Ridsdale, Megan PayneMegan Payne, Kate J Heesom, Marieangela C Wilson, Andrew Davidson, Alexander Greenhough, Sara Davies, Ann C Williams, Allison Blair, Marian L Waterman, Alex Tonks, Richard L DarleyCanonical Wnt/ß-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized ß-catenin is indicative of active Wnt signaling and is frequently observed in acute myeloid leukemia patients; however, some patients exhibit little or no nuclear ß-catenin even where cytosolic ß-catenin is abundant. Control of the subcellular localization of ß-catenin therefore represents an additional mechanism regulating Wnt signaling in hematopoietic cells. To investigate the factors mediating the nuclear-localization of ß-catenin we carried out the first nuclear/cytoplasmic proteomic analysis of the ß-catenin interactome in myeloid leukemia cells and identified putative novel ß-catenin interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear ß-catenin) versus Wnt-unresponsive cells (low nuclear ß-catenin) suggested the transcriptional partner, LEF-1, could direct the nuclear-localization of ß-catenin. The relative levels of nuclear LEF-1 and ß-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF-1 knockdown perturbed ß-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF-1 overexpression was able to promote both nuclear-localization and ß-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This is the first ß-catenin interactome study in hematopoietic cells and reveals LEF-1 as a mediator of nuclear ß-catenin level human myeloid leukemia.
Funding
Targeting nuclear localisation of B-catenin in acute leukaemia; G2445; The Kay Kendall Leukaemia Fund (KKLF); KKL1051
History
Publication status
- Published
File Version
- Published version
Journal
HaematologicaISSN
1592-8721Publisher
Ferrata Storti FoundationExternal DOI
Issue
7Volume
104Page range
1365-1377Department affiliated with
- Biochemistry Publications
Research groups affiliated with
- Haematology Research Group Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2019-01-09First Open Access (FOA) Date
2019-01-09First Compliant Deposit (FCD) Date
2019-01-03Usage metrics
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