title: Interleukin-3-mediated regulation of β-catenin in myeloid transformation and acute myeloid leukemia.
abstract: Aberrant activation of β-catenin is a common event in AML and is an independent predictor of poor prognosis. Although increased β-catenin signaling in AML has been associated with oncogenic translocation products and activating mutations in the FLT3R, the mechanisms that activate β-catenin in AML more broadly are still unclear. Here, we describe a novel link between IL-3 signaling and the regulation of β-catenin in myeloid transformation and AML. In a murine model of HoxB8 and IL-3 cooperation, we show that β-catenin protein levels are modulated by IL-3 and that Cre-induced deletion of β-catenin abolishes IL-3-dependent growth and colony formation. In IL-3-dependent leukemic TF-1.8 cells, we observed increased β-catenin protein levels and nuclear localization in response to IL-3, and this correlated with transcriptional induction of β-catenin target genes. Furthermore, IL-3 promoted β-catenin accumulation in a subset of AML patient samples, and gene-expression profiling of these cells revealed induction of WNT/β-catenin and TCF4 gene signatures in an IL-3-dependent manner. This study is the first to link β-catenin activation to IL-3 and suggests that targeting IL-3 signaling may be an effective approach for the inhibition of β-catenin activity in some patients with AML.
authors.affiliation: Centre for Cancer Biology and School of Molecular and Biomedical Science and Centre for Stem Cell Research and Departments of Haematology and Department of Pharmacy and Medical Sciences, The University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Teresa
authors.initials: T
authors.lastname: Sadras
authors.affiliation: Centre for Cancer Biology and Departments of Haematology and School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia;
authors.forename: Michelle
authors.initials: M
authors.lastname: Perugini
authors.affiliation: Centre for Cancer Biology and Departments of Haematology and School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia;
authors.forename: Chung H
authors.initials: CH
authors.lastname: Kok
authors.affiliation: Centre for Cancer Biology and Departments of Haematology and Department of Pharmacy and Medical Sciences, The University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Iarossi
authors.affiliation: Centre for Cancer Biology and Immunology, SA Pathology, Adelaide, South Australia, Australia;
authors.forename: Susan L
authors.initials: SL
authors.lastname: Heatley
authors.affiliation: Division of Cell Signalling and Cell Death, Walter and Eliza Hall Institute, Parkville, Victoria, Australia; and.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Brumatti
authors.affiliation: Centre for Cancer Biology and School of Molecular and Biomedical Science and Centre for Stem Cell Research and Immunology, SA Pathology, Adelaide, South Australia, Australia;
authors.forename: Michael S
authors.initials: MS
authors.lastname: Samuel
authors.affiliation: Departments of Haematology and School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia;
authors.forename: Luen B
authors.initials: LB
authors.lastname: To
authors.affiliation: Centre for Cancer Biology and Departments of Haematology and School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia;
authors.forename: Ian D
authors.initials: ID
authors.lastname: Lewis
authors.affiliation: Centre for Cancer Biology and School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia; Immunology, SA Pathology, Adelaide, South Australia, Australia;
authors.forename: Angel F
authors.initials: AF
authors.lastname: Lopez
authors.affiliation: Division of Cell Signalling and Cell Death, Walter and Eliza Hall Institute, Parkville, Victoria, Australia; and.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Ekert
authors.affiliation: Centre for Cancer Biology and Immunology, SA Pathology, Adelaide, South Australia, Australia;
authors.forename: Hayley S
authors.initials: HS
authors.lastname: Ramshaw
authors.affiliation: Centre for Cancer Biology and School of Molecular and Biomedical Science and Centre for Stem Cell Research and Departments of Haematology and Department of Pharmacy and Medical Sciences, The University of South Australia, Adelaide, South Australia, Australia School of Medicine, The University of Adelaide, Adelaide, South Australia, Australia; richard.dandrea@unisa.edu.au.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: D'Andrea
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007377:Interleukin-3 / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C490669:HOXB8 protein, human; D018398:Homeodomain Proteins; C095822:Hoxb8 protein, mouse; C508596:IL3 protein, human; D007377:Interleukin-3; D009363:Neoplasm Proteins; C532096:TCF4 protein, human; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D014157:Transcription Factors; D051176:beta Catenin
keywords: Hox; gene-expression profiling; leukemic stem cell