EZH2 expression is dependent on MYC and TP53 regulation in diffuse large B‐cell lymphoma

Filho, Eduardo Henrique Cunha Neves; Hirth, Carlos Gustavo; Frederico, Igor Allen Sousa; Burbano, Rommel Rodrı́guez; Carneiro, Thiago Xavier; Rabenhorst, Sílvia Helena Barem

doi:10.1111/apm.13029

Cited by 9 publications

(7 citation statements)

References 29 publications

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“…Dardenne and colleagues [ 54 ] suggested an interaction between c-Myc and EZH2 ; they observed high levels of EZH2 activity in mouse models over-expressing N-Myc and in human PC cells, concluding that the histone methyltransferase EZH2 seems to cooperate with Myc in regulating its target genes in neuroendocrine prostate cancer. More recently, Neves Filho and colleagues [ 55 ] demonstrated that EZH2 was up-regulated by Myc and associated with high proliferation tumors in diffuse large-B-cell lymphoma. This a priori knowledge was used to include the above genes in our model.…”

Section: Discussionmentioning

confidence: 99%

Multi-Dimensional Scaling Analysis of Key Regulatory Genes in Prostate Cancer Using the TCGA Database

Boldrini

Faviana

Galli

et al. 2021

Genes

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Prostate cancer (PC) is a polygenic disease with multiple gene interactions. Therefore, a detailed analysis of its epidemiology and evaluation of risk factors can help to identify more accurate predictors of aggressive disease. We used the transcriptome data from a cohort of 243 patients from the Cancer Genome Atlas (TCGA) database. Key regulatory genes involved in proliferation activity, in the regulation of stress, and in the regulation of inflammation processes of the tumor microenvironment were selected to test a priori multi-dimensional scaling (MDS) models and create a combined score to better predict the patients’ survival and disease-free intervals. Survival was positively correlated with cortisol expression and negatively with Mini-Chromosome Maintenance 7 (MCM7) and Breast-Related Cancer Antigen2 (BRCA2) expression. The disease-free interval was negatively related to the expression of enhancer of zeste homolog 2 (EZH2), MCM7, BRCA2, and programmed cell death 1 ligand 1 (PD-L1). MDS suggested two separate pathways of activation in PC. Within these two dimensions three separate clusters emerged: (1) cortisol and brain-derived neurotrophic factor BDNF, (2) PD-L1 and cytotoxic-T-lymphocyte-associated protein 4 (CTL4); (3) and finally EZH2, MCM7, BRCA2, and c-Myc. We entered the three clusters of association shown in the MDS in several Kaplan–Meier analyses. It was found that only Cluster 3 was significantly related to the interval-disease free, indicating that patients with an overall higher activity of regulatory genes of proliferation and DNA repair had a lower probability to have a longer disease-free time. In conclusion, our data study provided initial evidence that selecting patients with a high grade of proliferation and DNA repair activity could lead to an early identification of an aggressive PC with a potentials for metastatic development.

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Section: Discussionmentioning

confidence: 99%

Multi-Dimensional Scaling Analysis of Key Regulatory Genes in Prostate Cancer Using the TCGA Database

Boldrini

Faviana

Galli

et al. 2021

Genes

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“…Several biomarkers have been shown to predict the outcome of DLBCL, but only a few have clinical applicability, reinforcing the necessity to identify their pathways. In a previous publication, 4 changes in the interaction of MYC , BCL2 , BCL6 , and TP53 may imply in loss of cell proliferation and apoptotic control, impaired DNA-repair mechanisms and B-cell maturation disturbance. Furthermore, these intricate interactions seem to vary upon GC versus nGC subgroups, with different molecular pathways between both subtypes with variable clinical outcomes, suggesting that GC and nGC phenotypes and their characteristic biological profile should be considered as two different entities.…”

Section: Introductionmentioning

confidence: 87%

Prognostic impact of miR-125b and miR-155b and their relationship with <i>MYC</i> and <i>TP53</i> in diffuse large B-cell lymphoma: cell-of-origin classification matters

Filho,

Zancheta,

de Barros Silva

et al. 2023

J Clin Exp Hematopathol

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Tumoral microRNAs, such as miR-125b and miR-155b, are important gene expression regulators with complex pathogenetic mechanisms. However, their role in DLBCL, especially when cell-of-origin classification is considered, are still to be elucidated. In a series of 139 DLBCL cases considering germinal center (GC) versus nonGC subtypes, we investigated miR-125b and miR-155b expression by in situ hibridization and their association with some immunophenotypic presentations, including MYC, BCL2 and TP53 expression, MYC, BCL2 and BCL6 translocation status, as well as clinicopathological features and outcomes. miR-125b detection was positively correlated to the Ki-67 index (P = 0.035) in the nGC. Considering the GC subgroup, the percentage of miR-125b positive cells was also correlated to either MYC and MYC/BCL2 double expression (P = 0.047 and P = 0.049, respectively). When it comes to nGC patients, miR-155b percentage and intensity, as well as Allred score, were positively correlated to disease progression (P = 0.038, P = 0.057 and P = 0.039, respectively). In a multivariate analysis, GC phenotype was a significant independent factor associated with higher OS (P = 0.007) and, considering the nGC group, although not significant, the expression of TP53, miR-125b and miR-155b seems to be potential prognostic biomarkers in these tumors. This study demonstrated different pathways based on cell-of-origin classification and highlighted different clinical outcomes. miR-125b, miR-155b and TP53 expression may also represent potential prognostic factors in nGC-DLBCL.

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“…Moreover, MUM1 higher expression was an independent predictive factor for progression (69) and was associated with poor OS and PFS (70). In DLBCL groups, EZH2 positivity was related to MUM1 expression, which favored a non-germinal center-like phenotype (41). MYC is responsible for EZH2 up-regulation through EZH2-targeting miRNAs, i.e., miR-26a, miR-26b, or miR-101 (71,72).…”

Section: Immunohistochemical Profile Of Follicular Lymphoma (Fl): (A)...mentioning

confidence: 99%

“…There are only a few publications in which EZH2 expression profile has been presented (29,60). Some studies are convincing that high EZH2 protein levels, i.e., in Burkitt lymphoma, DLBCL, highgrade FL, correlate with increased proliferation, aggressiveness, and poor prognosis (29,39,41,43). Those observations are practically ignoring the role of EZH2 in germinal center B cell development.…”

Section: Immunohistochemical Profile Of Follicular Lymphoma (Fl): (A)...mentioning

confidence: 99%

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EZH2 Expression in Follicular Lymphoma Is Variable and Independent from the Progression of Disease Within 24 Months of First Treatment

et al. 2020

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Background/Aim: Follicular lymphoma (FL) relapse within 24 months of the first immunochemotherapy (POD24) indicates more precisely poor overall survival and high risk of death. The aim of the study was to assess the potential value of POD24 in FL and describe the enhancer of zeste homolog 2 (EZH2) expression profile, in correlation with clinical/ histopathological/immunophenotypical characteristics. Materials and Methods: This retrospective single-center study included 75 patients with FL treated under watch and wait (W&W) and immunochemotherapy regimens. All cases were immunohistochemically assessed: assays were performed for EZH2, CD10, BCL6, BCL2, MUM1, MYC and p53. Results: POD24 was independent of clinical/histopathological/ immunohistochemical features and separated patients with inferior outcomes. EZH2 high expression was observed in high/low grade and follicular/diffuse FL patterns. BCL2negative (p=0.042) and MUM1 (p=0.039), MYC (p<0.001), p53 (p<0.001) -positive cases had significantly higher EZH2 expression. Conclusion: POD24 is currently the most useful tool for the identification of poor outlook patients. EZH2 is crucial in FL biology, but the value of its protein expression is limited as a prognostic factor. Follicular lymphoma (FL) is an indolent B-cell lymphoma, but early relapse after first-line therapy occurs in up to 20% of patients (1-3). Different prognostic markers have been evaluated; however, the follicular International Prognostic Index (FLIPI) is still the only reproducible tool (4, 5). Its molecular modifications have not been yet widely accessible, while the next-generation sequencing-based genetic evaluation of FL is not a routine part of a diagnostic examination (6-8). Recently, the progression of disease within 24 months of first treatment (POD24) was applied for the identification of FL high-risk patients (3, 9). Early treatment failure is predictive of poor overall survival (10) and seems to be independent of initial treatment modality (11). Available results indicating the association of POD24 with prognostic markers, i.e., reduced intratumoral immune infiltration, pre-treatment positronemission tomography-based staging, and molecular status, are still inconsistent and unsatisfactory (12,13).Enhancer of zeste homolog 2 (EZH2) is a histone-lysine Nmethyltransferase enzyme encoded by the EZH2 gene. It is a functional component of polycomb repressive complex 2 (PRC2) and catalyzes the methylation of histone H3 lysine 27 6685

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EZH2 expression is dependent on MYC and TP53 regulation in diffuse large B‐cell lymphoma

Cited by 9 publications

References 29 publications

Multi-Dimensional Scaling Analysis of Key Regulatory Genes in Prostate Cancer Using the TCGA Database

Multi-Dimensional Scaling Analysis of Key Regulatory Genes in Prostate Cancer Using the TCGA Database

Prognostic impact of miR-125b and miR-155b and their relationship with <i>MYC</i> and <i>TP53</i> in diffuse large B-cell lymphoma: cell-of-origin classification matters

EZH2 Expression in Follicular Lymphoma Is Variable and Independent from the Progression of Disease Within 24 Months of First Treatment

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