title: Heterogeneous sensitivity of human acute myeloid leukemia to β-catenin down-modulation.
abstract: Dysregulation of the Wnt/β-catenin pathway has been observed in various malignancies, including acute myeloid leukemia (AML), where the overexpression of β-catenin is an independent adverse prognostic factor. β-catenin was found upregulated in the vast majority of AML samples and more frequently localized in the nucleus of leukemic stem cells compared with normal bone marrow CD34(+) cells. The knockdown of β-catenin, using a short hairpin RNA (shRNA) lentiviral approach, accelerates all-trans retinoic acid-induced differentiation and impairs the proliferation of HL60 leukemic cell line. Using in vivo quantitative tracking of these cells, we observed a reduced engraftment potential after xenotransplantation when β-catenin was silenced. However, when studying primary AML cells, despite effective downregulation of β-catenin we did not observe any impairment of their in vitro long-term maintenance on MS-5 stroma nor of their engraftment potential in vivo. Altogether, these results show that despite a frequent β-catenin upregulation in AML, leukemia-initiating cells might not be 'addicted' to this pathway and thus targeted therapy against β-catenin might not be successful in all patients.
authors.affiliation: Cancer Research UK Haematopoietic Stem Cell Group, London Research Institute, Cancer Research UK, London, UK.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Gandillet
authors.affiliation: Cancer Research UK Haematopoietic Stem Cell Group, London Research Institute, Cancer Research UK, London, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Park
authors.affiliation: Cancer Research UK Haematopoietic Stem Cell Group, London Research Institute, Cancer Research UK, London, UK.
authors.forename: François
authors.initials: F
authors.lastname: Lassailly
authors.affiliation: Cancer Research UK Haematopoietic Stem Cell Group, London Research Institute, Cancer Research UK, London, UK.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Griessinger
authors.affiliation: Cancer Research UK Haematopoietic Stem Cell Group, London Research Institute, Cancer Research UK, London, UK.
authors.forename: Jacques
authors.initials: J
authors.lastname: Vargaftig
authors.affiliation: Flow Cytometry Core Facility, London Research Institute, Cancer Research UK, London, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Filby
authors.affiliation: Department of Medical Oncology, St. Bartholomew's hospital, Queen Mary University of London, London, UK.
authors.forename: T Andrew
authors.initials: TA
authors.lastname: Lister
authors.affiliation: Cancer Research UK Haematopoietic Stem Cell Group, London Research Institute, Cancer Research UK, London, UK.
authors.forename: Dominique
authors.initials: D
authors.lastname: Bonnet
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002453:Cell Cycle; D002454:Cell Differentiation; D049109:Cell Proliferation; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D012333:RNA, Messenger; D034741:RNA, Small Interfering; D051176:beta Catenin