Background Diffuse Large B cell Lymphomas (DLBCLs) are among the most aggressive and frequently observed Non-Hodgkin lymphomas (NHLs). They are 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. The BTB/POZ domain transcription factor PATZ1 is a crucial negative regulator of BCL6 and Patz1-knockout mice develop B cell neoplasias expressing BCL6. Materials and methods The expression of PATZ1 and BCL6 has been studied by immunohistochemical staining of a Tissue-Micro-Array, including 70 Follicular lymphomas (FLs) and 100 DLBCLs. The Pearson's 2 test was used, where appropriate, to establish whether there were any relationships between the frequencies of PATZ1 expression in nuclear compartment and BCL6, histotypes and specific subtypes in DLBCL category. To assess the impact of PATZ1 expression on patients’ outcome, we analysed overall (OS) and progression-free (PFS) survival of DLBCL patients treated with Rituximab plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) chemotherapy. Kaplan-Meier survival curves were used to analyze OS and PFS. Statistical significance was assessed by the logrank test. Results and discussion We found that PATZ1 nuclear expression is significantly downregulated in FLs and DLBCLs, supporting a tumor suppressor role in these neoplasias. Moreover, consistent with previous results showing a direct downregulation of BCL6 transcription by PATZ1, we show that low PATZ1 nuclear expression significantly correlates with high BCL6 expression, mainly in DLBCLs. Finally, a significant correlation between low levels of PATZ1 and a worst outcome in DLBCLs patients treated with R-CHOP was observed. By analyzing the clinical and protein expression data available for the patients in which low expression of PATZ1 was correlated with a worse PFS following R-CHOP therapy, we found that most of them (84%) have high expression of BCL6 protein, supporting in these patients the negative regulation of BCL6 by PATZ1, but no evident correlation was observed with IPI code and cell of origin. These data suggest that, independently from some major known prognostic markers, such as IPI and cell of origin, PATZ1 expression could be evaluated as an additional marker to predict clinical outcome following R-CHOP therapy. Conclusions We have confirmed a crucial role for PATZ1 in human lymphomas, showing it behaves as a tumor suppressor gene in a subset of NHLs. Moreover we suggest it could be useful as an independent prognostic marker in BCL6-positive samples of DLBCL patients to gain further insight on the possible success of the R-CHOP therapy.
PATZ1 is a new prognostic marker of diffuse large B cell lymphomas
Vitiello, M.;Cerchia, L.;Fedele, M.
2016
Abstract
Background Diffuse Large B cell Lymphomas (DLBCLs) are among the most aggressive and frequently observed Non-Hodgkin lymphomas (NHLs). They are 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. The BTB/POZ domain transcription factor PATZ1 is a crucial negative regulator of BCL6 and Patz1-knockout mice develop B cell neoplasias expressing BCL6. Materials and methods The expression of PATZ1 and BCL6 has been studied by immunohistochemical staining of a Tissue-Micro-Array, including 70 Follicular lymphomas (FLs) and 100 DLBCLs. The Pearson's 2 test was used, where appropriate, to establish whether there were any relationships between the frequencies of PATZ1 expression in nuclear compartment and BCL6, histotypes and specific subtypes in DLBCL category. To assess the impact of PATZ1 expression on patients’ outcome, we analysed overall (OS) and progression-free (PFS) survival of DLBCL patients treated with Rituximab plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) chemotherapy. Kaplan-Meier survival curves were used to analyze OS and PFS. Statistical significance was assessed by the logrank test. Results and discussion We found that PATZ1 nuclear expression is significantly downregulated in FLs and DLBCLs, supporting a tumor suppressor role in these neoplasias. Moreover, consistent with previous results showing a direct downregulation of BCL6 transcription by PATZ1, we show that low PATZ1 nuclear expression significantly correlates with high BCL6 expression, mainly in DLBCLs. Finally, a significant correlation between low levels of PATZ1 and a worst outcome in DLBCLs patients treated with R-CHOP was observed. By analyzing the clinical and protein expression data available for the patients in which low expression of PATZ1 was correlated with a worse PFS following R-CHOP therapy, we found that most of them (84%) have high expression of BCL6 protein, supporting in these patients the negative regulation of BCL6 by PATZ1, but no evident correlation was observed with IPI code and cell of origin. These data suggest that, independently from some major known prognostic markers, such as IPI and cell of origin, PATZ1 expression could be evaluated as an additional marker to predict clinical outcome following R-CHOP therapy. Conclusions We have confirmed a crucial role for PATZ1 in human lymphomas, showing it behaves as a tumor suppressor gene in a subset of NHLs. Moreover we suggest it could be useful as an independent prognostic marker in BCL6-positive samples of DLBCL patients to gain further insight on the possible success of the R-CHOP therapy.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
