title: MicroRNA-128-3p is a novel oncomiR targeting PHF6 in T-cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia arises from the leukemic transformation of developing thymocytes and results from cooperative genetic lesions. Inactivation of the PHF6 gene is frequently observed in T-cell acute lymphoblastic leukemia, suggesting an important tumor suppressive role for PHF6 in the pathobiology of this leukemia. Although the precise function of PHF6 is still unknown, this gene is most likely involved in chromatin regulation, a strongly emerging theme in T-cell acute lymphoblastic leukemia. In this context, our previous description of a cooperative microRNA regulatory network controlling several well-known T-cell acute lymphoblastic leukemia tumor suppressor genes, including PHF6, is of great importance. Given the high frequency of PHF6 lesions in T-cell acute lymphoblastic leukemia and the integration of PHF6 in this microRNA regulatory network, we aimed to identify novel oncogenic microRNAs in T-cell acute lymphoblastic leukemia which suppress PHF6. To this end, we performed an unbiased PHF6 3'UTR-microRNA library screen and combined the results with microRNA profiling data of samples from patients with T-cell acute lymphoblastic leukemia and normal thymocyte subsets. We selected miR-128-3p as a candidate PHF6-targeting, oncogenic microRNA and demonstrated regulation of PHF6 expression upon modulation of this microRNA in T-cell acute lymphoblastic leukemia cell lines. In vivo evidence of an oncogenic role of this microRNA in T-cell acute lymphoblastic leukemia was obtained through accelerated leukemia onset in a NOTCH1-induced T-cell acute lymphoblastic leukemia mouse model upon miR-128-3p over-expression. We conclude that miR-128-3p is a strong novel candidate oncogenic microRNA in T-cell acute lymphoblastic leukemia which targets the PHF6 tumor suppressor gene.
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium.
authors.forename: Evelien
authors.initials: E
authors.lastname: Mets
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Van Peer
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium.
authors.forename: Joni
authors.initials: J
authors.lastname: Van der Meulen
authors.affiliation: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boice
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University Hospital, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.affiliation: Unit for Molecular Oncology, Inflammation Research Center, VIB, Ghent, Belgium Department for Molecular Biomedical Research, Ghent University, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Goossens
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Mestdagh
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Benoit
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Belgium.
authors.forename: Barbara
authors.initials: B
authors.lastname: De Moerloose
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium.
authors.forename: Nadine
authors.initials: N
authors.lastname: Van Roy
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium.
authors.forename: Bruce
authors.initials: B
authors.lastname: Poppe
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.affiliation: Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Hans-Guido
authors.initials: HG
authors.lastname: Wendel
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium franki.speleman@ugent.be Pieter.Rondou@ugent.be.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Center for Medical Genetics, Ghent University, Belgium franki.speleman@ugent.be Pieter.Rondou@ugent.be.
authors.forename: Pieter
authors.initials: P
authors.lastname: Rondou
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D018390:Gene Targeting / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis* / Q000235:genetics*; D012097:Repressor Proteins
chemical_list: D002352:Carrier Proteins; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; C502542:PHF6 protein, human; D012097:Repressor Proteins