Oncogenic role of Pax5 in the T-lymphoid lineage upon ectopic expression from the immunoglobulin heavy-chain locus

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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-lymphoid PAX5 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 IgHP5ki 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 IgHP5ki/+ and IgHP5ki/P5ki mice. Aggressive T-cell lymphomas develop even faster in IkPax5/+ 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.