Abstract
Four of 9 PAX transcription factor genes have been associated with chromosomal translocations in human tumors, although their oncogenic potential has not yet been demonstrated in transgenic mouse models. The B-lymphoidPAX5 gene participates in the generation of the t(9;14)(p13;q32) translocation in germinal center B cells, which leads to deregulated PAX5 expression under the control of the immunoglobulin heavy-chain (IgH) locus in a subset of B-cell non-Hodgkin lymphomas. Here we reconstructed a human t(9;14) translocation in a knock-in mouse by inserting a PAX5 minigene into the IgH locus. The IgH(P5ki) allele, which corresponds to a germline rather than somatic mutation, is activated in multipotent hematopoietic progenitors and is subsequently expressed in dendritic cells (DCs) and in natural killer (NK), T, and B cells. Ectopic Pax5 expression interferes with normal T-cell development and causes immature T-lymphoblastic lymphomas in IgH(P5ki/+) and IgH(P5ki/P5ki) mice. Aggressive T-cell lymphomas develop even faster in Ik(Pax5/+) mice expressing Pax5 from the Ikaros locus. Pax5 expression in thymocytes activates B-cell-specific genes and represses T-lymphoid genes, suggesting that Pax5 contributes to lymphomagenesis by deregulating the T-cell gene-expression program. These data identify Pax5 as a potent oncogene and demonstrate that the T-lymphoid lineage is particularly sensitive to the oncogenic action of Pax5.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Alleles
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Animals
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B-Lymphocytes / metabolism
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B-Lymphocytes / pathology
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Bone Marrow Transplantation
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Cell Differentiation / genetics*
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Cell Lineage
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Cell Transformation, Neoplastic / genetics*
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Chromosomes, Human, Pair 14 / genetics*
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Chromosomes, Human, Pair 14 / ultrastructure
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Chromosomes, Human, Pair 9 / genetics*
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Chromosomes, Human, Pair 9 / ultrastructure
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Dendritic Cells / metabolism
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Dendritic Cells / pathology
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Embryonal Carcinoma Stem Cells
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Gene Expression Regulation, Neoplastic
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Humans
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Ikaros Transcription Factor / genetics
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Immunoglobulin Heavy Chains / genetics*
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Killer Cells, Natural / metabolism
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Killer Cells, Natural / pathology
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Lymphocytes / metabolism
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Lymphocytes / pathology
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Lymphoma, B-Cell / genetics
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Lymphoma, B-Cell / pathology
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Mice
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Mice, Inbred C57BL
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Mutagenesis, Insertional
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Neoplasm Transplantation
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Neoplastic Stem Cells / metabolism
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Neoplastic Stem Cells / pathology*
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PAX5 Transcription Factor / genetics
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PAX5 Transcription Factor / physiology*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
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Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
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Promoter Regions, Genetic*
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Radiation Chimera
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T-Lymphocytes / metabolism
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T-Lymphocytes / pathology*
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Translocation, Genetic*
Substances
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Immunoglobulin Heavy Chains
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PAX5 Transcription Factor
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PAX5 protein, human
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Pax5 protein, mouse
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Zfpn1a1 protein, mouse
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Ikaros Transcription Factor