Dataset Information

Characterisation of the Beta-Catenin cytoplasmic/nuclear interactome in leukaemia cells

ABSTRACT: Canonical Wnt/B-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 (AML) patients; however, some patients exhibit little or no β-catenin nuclear-localization even where cytosolic B-catenin is abundant. Differential propensity for nuclear-localized β-catenin is also observed in cell lines. To investigate the factors mediating the nuclear-localization of B-catenin we carried out a nuclear/cytoplasmic proteomic analysis of the B-catenin interactome in myeloid leukemia cells. From this we identified hundreds of putative novel B-catenin-interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear B-catenin, K562/HEL) versus Wnt-unresponsive cells (low nuclear B-catenin, ML1) suggested the established interactor, LEF1, is a key factor mediating the nuclear-localization of B-catenin in myeloid leukemia. The relative levels of nuclear LEF1 and B-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF1 knockdown inhibited B-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF1 overexpression was able to promote both nuclear-localization and B-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This study is the first to present a B-catenin interactome in hematopoietic cells and reveals LEF1 as a critical regulator of canonical Wnt signaling in myeloid leukemia.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Myeloid Leukocyte, Myelocytic Leukemia Cell Line, Monocyte, Granulocyte

DISEASE(S): Acute Myeloid Leukemia,Chronic Myeloid Leukemia

SUBMITTER: Rhys Morgan

LAB HEAD: Rhys Gareth Morgan

PROVIDER: PXD009305 | Pride | 2019-01-11

REPOSITORIES: Pride

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Publications

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

Morgan Rhys G RG Ridsdale Jenna J Payne Megan M Heesom Kate J KJ Wilson Marieangela C MC Davidson Andrew A Greenhough Alexander A Davies Sara S Williams Ann C AC Blair Allison A Waterman Marian L ML Tonks Alex A Darley Richard L RL

Haematologica 20190110 7

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 (AML) 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 ...[more]

PMID: 30630973

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