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LEF-1 drives aberrant ß-catenin nuclear localization in myeloid leukemia cells

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Version 2 2023-06-12, 08:57
Version 1 2023-06-09, 16:25
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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 Darley
Canonical 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

Haematologica

ISSN

1592-8721

Publisher

Ferrata Storti Foundation

Issue

7

Volume

104

Page range

1365-1377

Department affiliated with

  • Biochemistry Publications

Research groups affiliated with

  • Haematology Research Group Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2019-01-09

First Open Access (FOA) Date

2019-01-09

First Compliant Deposit (FCD) Date

2019-01-03

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