title: Characterization of a set of tumor suppressor microRNAs in T cell acute lymphoblastic leukemia.
abstract: The posttranscriptional control of gene expression by microRNAs (miRNAs) is highly redundant, and compensatory effects limit the consequences of the inactivation of individual miRNAs. This implies that only a few miRNAs can function as effective tumor suppressors. It is also the basis of our strategy to define functionally relevant miRNA target genes that are not under redundant control by other miRNAs. We identified a functionally interconnected group of miRNAs that exhibited a reduced abundance in leukemia cells from patients with T cell acute lymphoblastic leukemia (T-ALL). To pinpoint relevant target genes, we applied a machine learning approach to eliminate genes that were subject to redundant miRNA-mediated control and to identify those genes that were exclusively targeted by tumor-suppressive miRNAs. This strategy revealed the convergence of a small group of tumor suppressor miRNAs on the Myb oncogene, as well as their effects on HBP1, which encodes a transcription factor. The expression of both genes was increased in T-ALL patient samples, and each gene promoted the progression of T-ALL in mice. Hence, our systematic analysis of tumor suppressor miRNA action identified a widespread mechanism of oncogene activation in T-ALL.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Viraj R
authors.initials: VR
authors.lastname: Sanghvi
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Konstantinos J
authors.initials: KJ
authors.lastname: Mavrakis
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Joni
authors.initials: J
authors.lastname: Van der Meulen
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Boice
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Wolfe
authors.affiliation: Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA. Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Carty
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Prathibha
authors.initials: P
authors.lastname: Mohan
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Rondou
authors.affiliation: Computational Biology Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Socci
authors.affiliation: Department of Pediatric Hematology-Oncology, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Benoit
authors.affiliation: Department of Clinical Chemistry, Microbiology and Immunology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Taghon
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Van Vlierberghe
authors.affiliation: Computational Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
authors.forename: Christina S
authors.initials: CS
authors.lastname: Leslie
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. wendelh@mskcc.org.
authors.forename: Hans-Guido
authors.initials: HG
authors.lastname: Wendel
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D001185:Artificial Intelligence; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016147:Genes, Tumor Suppressor; D020570:Genes, myb / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006609:High Mobility Group Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000378:metabolism
chemical_list: C486329:Hbp1 protein, mouse; D006609:High Mobility Group Proteins; D035683:MicroRNAs; D012097:Repressor Proteins