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

Haematologica. 2019 Jul;104(7):1365-1377. doi: 10.3324/haematol.2018.202846. Epub 2019 Jan 10.

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 (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 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 in human myeloid leukemia.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Cell Nucleus / metabolism*
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Leukemia, Myeloid, Acute / genetics
  • Leukemia, Myeloid, Acute / metabolism*
  • Leukemia, Myeloid, Acute / pathology
  • Lymphoid Enhancer-Binding Factor 1 / antagonists & inhibitors
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Lymphoid Enhancer-Binding Factor 1 / metabolism*
  • Myelodysplastic Syndromes / metabolism*
  • Myelodysplastic Syndromes / pathology
  • Protein Interaction Domains and Motifs
  • Proteome / analysis*
  • RNA, Small Interfering / genetics
  • Transcriptional Activation
  • Tumor Cells, Cultured
  • Wnt1 Protein / genetics
  • Wnt1 Protein / metabolism*
  • beta Catenin / genetics
  • beta Catenin / metabolism*

Substances

  • Biomarkers, Tumor
  • CTNNB1 protein, human
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • Proteome
  • RNA, Small Interfering
  • WNT1 protein, human
  • Wnt1 Protein
  • beta Catenin