In aggressive variants of non-Hodgkin lymphomas, Ezh2 is strongly expressed and polycomb repressive complex PRC1.4 dominates over PRC1.2

Abstract

Polycomb group (PcG) proteins are important for the regulation of hematopoiesis by regulating chromatin compaction and silencing genes related to differentiation and cell cycle. Overexpression of enhancer of zeste homologue 2 (Ezh2) and Bmi-1/PCGF4 has been implicated in solid organ cancers, while Mel-18/PCGF2 has been reported as a tumor suppressor. Detailed expression profiles of PcG proteins and their diagnostic significance in malignant lymphomas are still unknown. In this study, we analyzed the expression levels of Ezh2, Bmi-1, Mel-18, and Ki67 in 197 Hodgkin's and non-Hodgkin's lymphoma patient samples and in lymphoma cell lines using immunohistochemistry, fluorescent immunocytochemistry, and Western blotting. Immunohistochemical staining showed that Ezh2 expression was significantly increased in aggressive compared to indolent subtypes of B cell neoplasms (P = 0.000-0.030), while no significant differences in Bmi-1 expression were found between these subtypes. Compared to the normal counterpart, T cell lymphomas showed significant overexpression of Bmi-1 (P = 0.011) and Ezh2 (P = 0.000). The Ki67 labeling index showed a positive correlation with Ezh2 expression in B cell lymphomas (correlation coefficient (Co) = 0.983, P = 0.000) and T/NK cell lymphomas (Co = 0.629, P = 0.000). Fluorescent immunohistochemical staining showed coexpression of Ezh2 and Ki67 in the same tumor cells, indicating that Ezh2 expression correlates with cell proliferation. Both B and T/NK cell neoplasms showed low expression of Mel-18 and high expression of both Bmi-1 and Ezh2. In conclusion, in aggressive lymphoma variants, Ezh2 is strongly expressed and polycomb repressive complex PRC1.4 dominates over PRC1.2. Coexpression of Bmi-1 and Ezh2 is a characteristic of aggressive lymphomas. Ezh2 correlates with the proliferation and aggressive nature of non-Hodgkin's lymphomas.

BMI-1, a promising therapeutic target for human cancer

“…Overexpression of BMI-1 has been previously reported in gastric, ovarian, breast, head and neck, pancreatic and lung cancer, as well as in primary hepatocellular carcinoma (HCC) and endometrial carcinoma (8)(9)(10)(11)(12)(13)(14)(15)(16). In addition, BMI-1 overexpression has been identified in patients suffering from myelodysplastic syndrome, chronic myeloid leukemia, acute myeloid leukemia and lymphoma (17)(18)(19)(20). Previous studies have indicated that the increased BMI-1 expression was associated with tumor proliferation, invasion/metastasis, chemosensitivity and patient survival (Table I).…”

“…Certain in vitro studies revealed that overexpression of BMI-1 can promote chemoresistance (23), whereas depletion of BMI-1 is able to enhance the chemosensitivity of HCC (15,37) and ovarian cancer cells (38,39). In a clinical setting, the overexpression of BMI-1 may facilitate drug resistance in hematological malignancies, including the myelodysplastic syndrome, chronic myeloid leukemia, acute myeloid leukemia and lymphoma (17)(18)(19)(20)40). In addition, BMI-1 has been demonstrated to play an important role in chemoresistance and radiosensitivity in breast cancer (41,42).…”

Polycomb genes, miRNA, and their deregulation in B-cell malignancies

“…26 Expression of EZH2 strongly associates with B-cell malignancies, with its high levels correlated with the Ki67 labeling index, lymphoma aggressiveness, and unfavorable prognosis. 33,34 The highest percentage of EZH2 positivity was found in 100% of Burkitt lymphomas, 87.5% of grade-3 FLs, and 85.7% of DLBCLs. Multivariate survival analysis identified EZH2 as the strongest prognostic predictor of inferior outcomes of MCLs.…”

“…31,32 In human B-cell lymphomas, BMI1 overexpression is common in almost all subtypes. 33 Expression of BMI1 alone or in combination with EZH2 characterizes aggressive B-cell lymphomas with unfavorable prognosis. 27,33,34 Recently, a novel t(10;14)(p12;q32) translocation was identified in chronic lymphocytic leukemia and MCLs leading to IgH-BMI1 rearrangement and BMI1 overexpression 35 ; IgH-BMI1 rearrangement was acquired during tumor high-grade transformation and correlated with chemoresistance.…”

“…33 Expression of BMI1 alone or in combination with EZH2 characterizes aggressive B-cell lymphomas with unfavorable prognosis. 27,33,34 Recently, a novel t(10;14)(p12;q32) translocation was identified in chronic lymphocytic leukemia and MCLs leading to IgH-BMI1 rearrangement and BMI1 overexpression 35 ; IgH-BMI1 rearrangement was acquired during tumor high-grade transformation and correlated with chemoresistance. 35 Transcriptome analyses of multiple cancers found that BMI1-driven gene signatures define a phenotype of cancer stem cells, 36 suggesting that BMI1 confers malignant cells with features of cancer stem cells, the rare cancerous subpopulations that confer drug resistance and regeneration abilities.…”