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Loss of p73 promotes dissemination of Myc-induced B cell lymphomas in mice

2010-06-01 22:14:43

The Journal of Clinical Investigation; 2010 June; 120(6):2070-80


Alice Nemajerova, Oleksi Petrenko, Lorenz Trümper, Gustavo Palacios, and Ute M. Moll



Introduction



The p73 gene was identified through its structural homology with the p53 tumor suppressor. Initial overexpression studies demonstrated that p73 can activate many p53-responsive genes and partly substitute for p53 in triggering cell-cycle arrest or apoptosis. However, p73 and p53 are not functionally equivalent. Recent analyses revealed that p73 has its own set of transcriptional target genes. Moreover, the TP73 gene locus is complex and encodes 2 classes of isoforms with opposing activities. p73 variants that lack the N-terminal transactivation (TA) domain function to interfere with the activity of the full-length counterparts of p73, p53, and p63. A net upregulation of the dominant negative ΔNp73 isoforms (i.e., a high ΔN/TAp73 ratio) frequently occurs in carcinomas and is a poor prognostic marker in some solid tumors.



Although p53 and p73 share structural similarities, their differences in vivo are striking. Thus, p53-null mice are developmentally normal but show a high predisposition to spontaneous tumors, mainly T lymphomas. In contrast, in vivo evidence for a tumor-suppressor role of p73 is still scarce and contradictory. p73-knockout mice (which lack all p73 isoforms) are born with developmental neurological and immunological defects associated with early lethality, but show no tumor predisposition. Flores et al. reported spontaneous development of mainly microscopic tumors in p73+/– and p73–/– mice, particularly when combined with p53 heterozygosity, while p73 did not contribute to p53 suppressor activity during irradiation-induced T cell lymphomagenesis. On the other hand, aging mice specifically lacking TAp73 develop spontaneous malignancies, mainly lung adenocarcinomas and lymphomas.



Unlike p53, the p73 gene is rarely mutated in human cancers. In fact, there is currently no compelling genetic evidence that inactivation of p73 is required for malignant transformation or progression in human tumors. The single notable exception comes from persistent reports of frequent loss of p73 expression in hematological malignancies. Specifically, inactivation of the p73 gene by epigenetic silencing or deletion is a common finding in malignant lymphoproliferative disorders. p73 is inactivated in about 35% of acute lymphoblastic leukemia (ALL) and about one-third of non-Hodgkin lymphomas (NHLs). Of note, 95% of human lymphomas are B cell in origin. Also, in a study of natural killer cell lymphomas, the p73 gene was methylated in 94% of cases. Assessment of p73 methylation may provide important prognostic information, as shown in patients with ALL. In sum, these data suggest that p73 might play a pathogenetic role in human lymphomas.



To experimentally assess the role of p73 in B cell lymphomagenesis, we investigated Eμ-myc transgenic mice, the well-characterized model of human NHL. These mice overexpress c-Myc in B cell progenitors under the control of the immunoglobulin heavy chain enhancer and develop pre–B cell and/or B cell lymphomas. The latent period prior to onset of disease reflects the ability of c-Myc to induce p53-dependent and p53-independent growth arrest and apoptotic checkpoints that protect animals against tumor formation. These checkpoints become disabled when overtly malignant cells emerge. Given the fact that a significant fraction of human B lymphomas exhibit deregulated c-Myc and p73 and that c-Myc activates proapoptotic functions of p73 in vitro, Eμ-myc mice provide a relevant in vivo model to assess the impact of p73 on tumor behavior.



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