title: A Sleeping Beauty screen reveals NF-kB activation in CLL mouse model.
abstract: TCL1 oncogene is overexpressed in aggressive form of human chronic lymphocytic leukemia (CLL) and its dysregulation in mouse B cells causes a CD5-positive leukemia similar to the aggressive form of human CLLs. To identify oncogenes that cooperate with Tcl1, we performed genetic screen in Eμ-TCL1 mice using Sleeping Beauty transposon-mediated mutagenesis. Analysis of transposon common insertion sites identified 7 genes activated by transposon insertions. Overexpression of these genes in mouse CLL was confirmed by real time reverse transcription-polymerase chain reaction. Interestingly, the main known function of 4 of 7 genes (Nfkb1, Tab2, Map3K14, and Nfkbid) is participation in or activation of the nuclear factor-kB (NF-kB) pathway. In addition, activation of the NF-kB is 1 of main functions of Akt2, also identified in the screen. These findings demonstrate cooperation of Tcl1 and the NF-kB pathway in the pathogenesis of aggressive CLL. Identification cooperating cancer genes will result in the development of combinatorial therapies to treat CLL.
authors.affiliation: Department of Molecular Virology, Immunology and Medical Genetics and Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Zanesi
authors.forename: Veronica
authors.initials: V
authors.lastname: Balatti
authors.forename: Jesse
authors.initials: J
authors.lastname: Riordan
authors.forename: Aaron
authors.initials: A
authors.lastname: Burch
authors.forename: Lara
authors.initials: L
authors.lastname: Rizzotto
authors.forename: Alexey
authors.initials: A
authors.lastname: Palamarchuk
authors.forename: Luciano
authors.initials: L
authors.lastname: Cascione
authors.forename: Alessandro
authors.initials: A
authors.lastname: Lagana
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Dupuy
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Yuri
authors.initials: Y
authors.lastname: Pekarsky
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology; D005820:Genetic Testing / Q000379:methods; D053208:Kaplan-Meier Estimate; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional / Q000379:methods; D052002:NF-kappa B p50 Subunit / Q000235:genetics* / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D019895:Transposases / Q000235:genetics; D000097782:NF-kappaB-Inducing Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D052002:NF-kappa B p50 Subunit; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D019895:Transposases; D000097782:NF-kappaB-Inducing Kinase; C498761:Tab2 protein, mouse; C490393:Tcl1 protein, mouse; C073701:Nfkb1 protein, mouse; C494471:sleeping beauty transposase, human