title: The interplay of autophagy and β-Catenin signaling regulates differentiation in acute myeloid leukemia.
abstract: The major feature of leukemic cells is an arrest of differentiation accompanied by highly active proliferation. In many subtypes of acute myeloid leukemia, these features are mediated by the aberrant Wnt/β-Catenin pathway. In our study, we established the lectin LecB as inducer of the differentiation of the acute myeloid leukemia cell line THP-1 and used it for the investigation of the involved processes. During differentiation, functional autophagy and low β-Catenin levels were essential. Corresponding to this, a high β-Catenin level stabilized proliferation and inhibited autophagy, resulting in low differentiation ability. Initiated by LecB, β-Catenin was degraded, autophagy became active and differentiation took place within hours. Remarkably, the reduction of β-Catenin sensitized THP-1 cells to the autophagy-stimulating mTOR inhibitors. As downmodulation of E-Cadherin was sufficient to significantly reduce LecB-mediated differentiation, we propose E-Cadherin as a crucial interaction partner in this signaling pathway. Upon LecB treatment, E-Cadherin colocalized with β-Catenin and thereby prevented the induction of β-Catenin target protein expression and proliferation. That way, our study provides for the first time a link between E-Cadherin, the aberrant Wnt/β-Catenin signaling, autophagy and differentiation in acute myeloid leukemia. Importantly, LecB was a valuable tool to elucidate the underlying molecular mechanisms of acute myeloid leukemia pathogenesis and may help to identify novel therapy approaches.
authors.affiliation: Faculty of Biology, Albert-Ludwigs-University Freiburg, Schänzlestraβe 1, 79104 Freiburg, Germany; BIOSS-Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Schänzlestraβe 18, 79104 Freiburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Kühn
authors.affiliation: Faculty of Biology, Albert-Ludwigs-University Freiburg, Schänzlestraβe 1, 79104 Freiburg, Germany; BIOSS-Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Schänzlestraβe 18, 79104 Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Cott
authors.affiliation: Faculty of Biology, Albert-Ludwigs-University Freiburg, Schänzlestraβe 1, 79104 Freiburg, Germany; BIOSS-Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Schänzlestraβe 18, 79104 Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Bohler
authors.affiliation: Faculty of Biology, Albert-Ludwigs-University Freiburg, Schänzlestraβe 1, 79104 Freiburg, Germany; BIOSS-Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Schänzlestraβe 18, 79104 Freiburg, Germany; International Max Planck Research School for Molecular and Cellular Biology (IMPRS-MCB), Max Planck Institute of Immunobiology and Epigenetics, Stübeweg 51, 79108 Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Aigal
authors.affiliation: Faculty of Biology, Albert-Ludwigs-University Freiburg, Schänzlestraβe 1, 79104 Freiburg, Germany; BIOSS-Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Schänzlestraβe 18, 79104 Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Zheng
authors.affiliation: Faculty of Biology, Albert-Ludwigs-University Freiburg, Schänzlestraβe 1, 79104 Freiburg, Germany; BIOSS-Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Schänzlestraβe 18, 79104 Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Villringer
authors.affiliation: Centre de Recherches sur les Macromolécules Végétales (CERMAV), CNRS and Université Grenoble Alpes , 601 rue de la chimie, 38000 Grenoble, France.
authors.forename: A
authors.initials: A
authors.lastname: Imberty
authors.affiliation: Faculty of Biology, Albert-Ludwigs-University Freiburg, Schänzlestraβe 1, 79104 Freiburg, Germany; BIOSS-Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Schänzlestraβe 18, 79104 Freiburg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Claudinon
authors.affiliation: Faculty of Biology, Albert-Ludwigs-University Freiburg, Schänzlestraβe 1, 79104 Freiburg, Germany; BIOSS-Centre for Biological Signalling Studies, Albert-Ludwigs-University Freiburg, Schänzlestraβe 18, 79104 Freiburg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Römer