Abstract
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.
Highlights
Non-Hodgkin Lymphoma (NHL), including 85% of B-Cell Lymphomas represents the most common haematological malignancy disorder [1]
One of the master oncogenes in this diffuse large B-cell lymphomas (DLBCLs) subgroup is B cell lymphoma 6 (BCL6), which is involved in several cell processes that can impact on the ability of the B-cell to differentiate and proliferate [12]
We have shown that the POZ/domain and kruppel zinc finger (POK) transcription factor PATZ1 plays a crucial role in the negative autoregulation of BCL6 expression, and that Patz1-knockout mice develop a thymus neoplastic phenotype caused by BCL6 overexpression, suggesting that PATZ1 could be involved in BCL6 expressing human B cell lymphomas [13]
Summary
Non-Hodgkin Lymphoma (NHL), including 85% of B-Cell Lymphomas represents the most common haematological malignancy disorder [1]. As for other members of the POK family, PATZ1 plays key roles in development and cancer through its involvement in a variety of cellular processes, including cell proliferation, DNA repair, senescence, apoptosis and differentiation [16,17,18,19,20,21,22]. In most of these processes it acts upstream and downstream of p53, suggesting it could be a key regulator of the p53 pathway [16, 18, 22]. We found that low PATZ1 (either gene or protein) expression significantly correlates with poor survival, suggesting PATZ1 as a negative prognostic marker for this heterogeneous malignancy
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