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Haematologica. 2019 Jan 10. pii: haematol.2018.202846. doi: 10.3324/haematol.2018.202846. [Epub ahead of print]

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

Author information

1
University of Sussex; rhys.morgan@sussex.ac.uk.
2
Cardiff University.
3
University of Sussex.
4
University of Bristol.
5
University of California, Irvine.

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.

KEYWORDS:

Acute Myeloid Leukemia; B-Catenin; LEF-1; Signal Transduction; Wnt Signaling

PMID:
30630973
DOI:
10.3324/haematol.2018.202846
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