PATZ1 expression correlates positively with BAX and negatively with BCL6 and survival in human diffuse large B cell lymphomas

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.

PATZ1 is a new prognostic marker of glioblastoma associated with the stem-like phenotype and enriched in the proneural subtype

“…Immunofluorescence analysis confirmed expression of PATZ1 in GSC growing either as spheres or in adhesion and their colocalization with the stemness marker Nestin (Figure 4E and data not shown). PATZ1 expression here appears mainly nuclear but a speckled cytosolic expression can be observed as previously described in other cancer cell types [ 20 – 22 ].…”

“…Sections were dewaxed in xylene, hydrated in graded series of alcohol and subjected to heat-induced antigen retrieval. After blocking endogenous peroxidase activity, the tissue was incubated with antibody anti-PATZ1 (polyclonal rabbit, R1P1 [ 22 ]; 1: 500 dilution, overnight incubation). Subsequently, the slices were rinsed and incubated with the biotinylated secondary antibody, at room temperature, for 30 minutes.…”

OSdlbcl: An online consensus survival analysis web server based on gene expression profiles of diffuse large B‐cell lymphoma

“…Independent validation across different cohorts is of great importance for biomarker development, and OSdlbcl is a web server that could facilitate the cross‐validation of the prognostic value of biomarkers across seven DLBCL cohorts. To determine the prognosis performance of OSdlbcl, we collected 23 previously published DLBCL prognostic factors at the mRNA or protein level and tested their prognostic power in OSdlbcl at the mRNA level (Table , Figure ) . The forest plots more effectively presented the comparison results from references and OSdlbcl (Figure ).…”

“…To determine the prognosis performance of OSdlbcl, we collected 23 previously published DLBCL prognostic factors at the mRNA or protein level and tested their prognostic power in OSdlbcl at the mRNA level (Table 2, Figure 1). 2,9,[26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] The forest plots more effectively presented the comparison results from references and OSdlbcl ( Figure S1). Results showed that about 52% (12 out of 23) of biomarkers have significant prognostic values in the combined cohorts, while the remaining biomarkers (11 out of 23) present significant prognostic values in one or more cohorts ( Table 2).…”

Structural analysis of the PATZ1 BTB domain homodimer

“…Another feature that is common to PATZ1 and BCL6 is their BTB domain-mediated localization to nuclear speckles (Huynh et al, 2000;Fedele et al, 2000;Franco et al, 2016). While PATZ1 interacts with the nuclear speckle-resident ubiquitin ligase RNF4, whether potential post-translational modifications owing to this interaction affect its stability is not known (Pero et al, 2002).…”