Differential expression of enhancer of zeste homolog 2 (EZH2) protein in small cell and aggressive B-cell non-Hodgkin lymphomas and differential regulation of EZH2 expression by p-ERK1/2 and MYC in aggressive B-cell lymphomas.
EZH2, a member of the polycomb protein group, is an important methyltransferase that is overexpressed in various neoplasms. We found that in small cell B-cell lymphomas, EZH2 is expressed in <40% of neoplastic cells, with heterogenous signal intensity. In aggressive B-cell lymphomas, 70-100% of tumor cells were positive for EZH2 expression with high signal intensity, which correlated with a high proliferation rate. We investigated the potential signaling molecules that regulate EZH2 overexpression in aggressive B-cell lymphomas and found that 80% of cases of EZH2-positive diffuse large B-cell lymphoma show high p-ERK1/2 expression (average ~57% tumor cell positivity). In contrast, only a small percentage of tumor cells (~10%) show p-ERK1/2 expression in Burkitt lymphoma and double hit lymphoma. On average, 91 and 76% of neoplastic cells were positive for MYC expression in Burkitt lymphoma and double hit lymphoma, respectively, while only 20% neoplastic cells were positive for MYC expression in diffuse large B-cell lymphoma. None of the aggressive B-cell lymphomas showed significant p-STAT3 expression in EZH2-overexpressed cases. The correlation of EZH2 expression with aggressive behavior and proliferation rate in B-cell neoplasms suggests that this molecule may function as an oncogenic protein in these neoplasms, with possible regulation by different signaling cascades in different types of aggressive B-cell lymphomas: p-ERK-related signaling in diffuse large B-cell lymphoma, and MYC-related signaling in Burkitt lymphoma and double hit lymphoma. Furthermore, EZH2 and associated signaling cascades may serve as therapeutic targets for the treatment of aggressive B-cell lymphomas.
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Xuejun
X
Tian
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Ashley
A
Pelton
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
Ali
A
Shahsafaei
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
David M
DM
Dorfman
D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D049109:Cell Proliferation; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000032:analysis*; D006801:Humans; D007150:Immunohistochemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D016393:Lymphoma, B-Cell / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis*; D048052:Mitogen-Activated Protein Kinase 3 / Q000032:analysis*; D010766:Phosphorylation; D016271:Proto-Oncogene Proteins c-myc / Q000032:analysis* / Q000235:genetics; D015398:Signal Transduction
D014408:Biomarkers, Tumor; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3