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

ABSTRACT: Canonical Wnt/?-catenin signaling is frequently dysregulated in myeloid leukemias and is implicated in leukemogenesis. Nuclear-localized ?-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 ?-catenin even where cytosolic ?-catenin is abundant. Control of the subcellular localization of ?-catenin therefore represents an additional mechanism regulating Wnt signaling in hematopoietic cells. To investigate the factors mediating the nuclear-localization of ?-catenin, we carried out the first nuclear/cytoplasmic proteomic analysis of the ?-catenin interactome in myeloid leukemia cells and identified putative novel ?-catenin interactors. Comparison of interacting factors between Wnt-responsive cells (high nuclear ?-catenin) versus Wnt-unresponsive cells (low nuclear ?-catenin) suggested the transcriptional partner, LEF-1, could direct the nuclear-localization of ?-catenin. The relative levels of nuclear LEF-1 and ?-catenin were tightly correlated in both cell lines and in primary AML blasts. Furthermore, LEF-1 knockdown perturbed ?-catenin nuclear-localization and transcriptional activation in Wnt-responsive cells. Conversely, LEF-1 overexpression was able to promote both nuclear-localization and ?-catenin-dependent transcriptional responses in previously Wnt-unresponsive cells. This is the first ?-catenin interactome study in hematopoietic cells and reveals LEF-1 as a mediator of nuclear ?- catenin level in human myeloid leukemia.

SUBMITTER: Morgan RG 

PROVIDER: S-EPMC6601079 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature