Notch Target Gene Deregulation and Maintenance of the Leukemogenic Phenotype Do Not Require RBP-Jκ in Ikaros Null Mice
Copyright policy )Notch Target Gene Deregulation and Maintenance of the Leukemogenic Phenotype Do Not Require RBP-Jκ in Ikaros Null Mice
Abstract Ikaros and Notch are transcriptional regulators essential for normal T cell development. Aberrant activation of Notch target genes is observed in Ikaros-deficient thymocytes as well as leukemia cell lines. However, it is not known whether Notch deregulation plays a preferential or obligatory role in the leukemia that arise in Ikaros null (Ik−/−) mice. To answer this question, the expression of the DNA-binding Notch target gene activator RBP-Jκ was abrogated in Ik−/− double-positive thymocytes. This was accomplished through conditional inactivation using CD4-Cre transgenic mice containing floxed RBP-Jκ alleles (RBPJfl/fl). Ik−/− × RBPJfl/fl × CD4-Cre+ transgenic mice develop clonal T cell populations in the thymus that escape to the periphery, with similar kinetics and penetrance as their CD4-Cre− counterparts. The clonal populations do not display increased RBP-Jκ expression compared with nontransformed thymocytes, suggesting there is no selection for clones that have not fully deleted RBP-Jκ. However, RBPJ-deficient clonal populations do not expand as aggressively as their RBPJ-sufficient counterparts, suggesting a qualitative role for deregulated Notch target gene activation in the leukemogenic process. Finally, these studies show that RBP-Jκ plays no role in Notch target gene repression in double-positive thymocytes but rather that it is Ikaros that is required for the repression of these genes at this critical stage of T cell development.
- Northwestern University United States
- Northwestern University Philippines
Mice, Knockout, Leukemia, Experimental, Receptors, Notch, Mice, Transgenic, Cell Line, Immunophenotyping, Mice, Inbred C57BL, Ikaros Transcription Factor, Mice, T-Lymphocyte Subsets, Cell Line, Tumor, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Gene Targeting, Animals, Gene Silencing
Mice, Knockout, Leukemia, Experimental, Receptors, Notch, Mice, Transgenic, Cell Line, Immunophenotyping, Mice, Inbred C57BL, Ikaros Transcription Factor, Mice, T-Lymphocyte Subsets, Cell Line, Tumor, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Gene Targeting, Animals, Gene Silencing
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