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

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