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

Rhys Morgan, Jenna Ridsdale, Megan Payne, Kate Heesom, Marieangela C Wilson, Andrew Davidson, Alexander Greenhough, Sara Davies, Ann Williams, Allison Blair, Marian L Waterman, Alex Tonks, Richard Darley

Research output: Contribution to journalArticle (Academic Journal)

6 Citations (Scopus)
319 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)1365-1377
Number of pages13
JournalHaematologica
Volume104
Issue number7
Early online date10 Jan 2019
DOIs
Publication statusPublished - 1 Jul 2019

Keywords

  • acute myeloid leukemia
  • B-Catenin
  • LEF-1
  • Signal transduction
  • WNT signaling

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