Oncogenic role of Pax5 in the T-lymphoid lineage upon ectopic expression from the immunoglobulin heavy-chain locus.
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.
Souabni
Abdallah
A
Research Institute of Molecular Pathology, Vienna Biocenter, Dr Bohr-Gasse 7, A-1030 Vienna, Austria.
Jochum
Wolfram
W
Busslinger
Meinrad
M
D000483:Alleles; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000235:genetics*; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics* / Q000648:ultrastructure; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics* / Q000648:ultrastructure; D003713:Dendritic Cells / Q000378:metabolism / Q000473:pathology; D054278:Embryonal Carcinoma Stem Cells; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007694:Killer Cells, Natural / Q000378:metabolism / Q000473:pathology; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016254:Mutagenesis, Insertional; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000502:physiology*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D011828:Radiation Chimera; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D014178:Translocation, Genetic
D007143:Immunoglobulin Heavy Chains; D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; C497282:Pax5 protein, mouse; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor