LEF-1 drives aberrant ß-catenin nuclear localization in myeloid leukemia cells.
Haematologica
; 104(7): 1365-1377, 2019 07.
Article
em En
| MEDLINE
| ID: mdl-30630973
ABSTRACT
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 (AML) 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 in human myeloid leukemia.
Texto completo:
1
Bases de dados:
MEDLINE
Assunto principal:
Síndromes Mielodisplásicas
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Leucemia Mieloide Aguda
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Núcleo Celular
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Proteoma
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Proteína Wnt1
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Beta Catenina
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Fator 1 de Ligação ao Facilitador Linfoide
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Haematologica
Ano de publicação:
2019
Tipo de documento:
Article