PATZ1 expression correlates positively with BAX and negatively with BCL6 and survival in human diffuse large B cell lymphomas
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Renato Franco1,2,*, Giosuè Scognamiglio1,*, Elena Valentino1, Michela Vitiello3, Antonio Luciano4, Giuseppe Palma4, Claudio Arra4, Elvira La Mantia1, Luigi Panico5, Valentina Tenneriello5, Antonello Pinto6, Ferdinando Frigeri6, Gaetana Capobianco6, Gerardo Botti1, Laura Cerchia3, Annarosaria De Chiara1, Monica Fedele3
1Surgical Pathology Unit, National Cancer Institute ‘Fondazione Giovanni Pascale’, IRCCS, Naples, Italy
2Pathology Unit, Second University of Naples, Naples, Italy
3Institute of Experimental Endocrinology and Oncology (IEOS), National Research Council (CNR), Naples, Italy
4Animal Facility, National Cancer Institute ‘Fondazione Giovanni Pascale’, IRCCS, Naples, Italy
5Pathology Unit, Hospital ‘S.G. Moscati’, Avellino, Italy
6Haematology-Oncology and Stem Cell Transplantation Unit, Department of Hematology, National Cancer Institute, Fondazione ‘G. Pascale’, IRCCS, Naples, Italy
*These authors share co-first authorship
Keywords: non-Hodgkin lymphomas, prognostic marker, PATZ1, tissue-microarray, DLBCL
Received: January 16, 2016 Accepted: July 18, 2016 Published: August 01, 2016
Non-Hodgkin lymphomas (NHLs) include a heterogeneous group of diseases, which differ in both cellular origin and clinical behavior. Among the aggressive malignancies of this group, the diffuse large B-cell lymphomas (DLBCLs) are the most frequently observed. They are themselves clinically and molecularly heterogeneous and have been further sub-divided in three sub-types according to different cell of origin, mechanisms of oncogenesis and clinical outcome. Among them, the germinal center B-cell-like (GCB) derives from the germinal center and expresses the BCL6 oncogene. We have previously shown that Patz1-knockout mice develop B-cell neoplasias, suggesting a tumor suppressor role for PATZ1 in human NHLs. Here, by immunohistochemical analysis of a tissue-microarray including 170 NHLs, we found that PATZ1 nuclear expression is down-regulated in follicular lymphomas and DLBCLs. Moreover, consistent with our previous results showing a PATZ1-dependent regulation of BCL6 and BAX transcription, we show that low PATZ1 nuclear expression significantly correlates with high BCL6 expression, mainly in DLBCLs, and with low BAX expression, also considering separately follicular lymphomas and DLBCLs. Finally, by analyzing overall and progression-free survival in DLBCL patients that underwent rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, low levels of PATZ1 were significantly associated to a worst outcome and demonstrated an independent prognostic factor in multivariate analysis, including known prognostic factors of DLBCL, IPI score and cell of origin (GCB/non-GCB). Therefore, we propose PATZ1 as a new prognostic marker of DLBCLs, which may act as a tumor suppressor by enhancing apoptosis through inhibiting and enhancing transcription of BCL6 and BAX, respectively.
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