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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Disease Models, Animal
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Gene Expression Regulation, Leukemic / physiology
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Genetic Testing / methods
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Kaplan-Meier Estimate
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Leukemia, Lymphocytic, Chronic, B-Cell / genetics*
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Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
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Leukemia, Lymphocytic, Chronic, B-Cell / mortality
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Mice
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Mice, Transgenic
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Mutagenesis, Insertional / methods
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NF-kappa B p50 Subunit / genetics*
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NF-kappa B p50 Subunit / metabolism*
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NF-kappaB-Inducing Kinase
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Protein Serine-Threonine Kinases / genetics
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Protein Serine-Threonine Kinases / metabolism
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Proto-Oncogene Proteins / genetics*
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Proto-Oncogene Proteins / metabolism*
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Signal Transduction / physiology
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Transposases / genetics
Substances
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Adaptor Proteins, Signal Transducing
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NF-kappa B p50 Subunit
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Proto-Oncogene Proteins
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Tab2 protein, mouse
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Tcl1 protein, mouse
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Nfkb1 protein, mouse
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Protein Serine-Threonine Kinases
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Transposases
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sleeping beauty transposase, human