Uniform Expression of Notch1, Suppressor of B-Cell–Specific Gene Expression, in Plasmablastic Lymphoma

Abstract

Although the loss of B-lineage-specific gene expression is a distinctive feature of plasmablastic lymphoma, the underlying mechanism remains poorly understood. A candidate for this mechanism is Notch1 signaling, which interferes with the activity of B-cell-specific transcription factors E2A and early B-cell factor and positively regulates the mammalian target of rapamycin (mTOR) pathway. To explore the mechanism of loss of B-cell phenotype by correlating expression of B-cell markers with that of Notch1 and downstream targets of the mTOR pathway in plasmablastic lymphoma. A combination of flow cytometric and immunohistochemical immunophenotyping techniques was used on 9 cases of plasmablastic lymphoma to correlate loss of B-cell markers with expression of Notch1 and downstream activation of the mTOR pathway. These results are compared with 5 cases of primary effusion lymphoma and 21 cases of plasma cell myeloma. Plasmablastic lymphoma cases exhibit nearly complete loss of B-cell-associated markers and uniform expression of Notch1, with a predominantly nuclear staining pattern. There is a concurrent activation of the mTOR pathway, indicated by expression of mTOR targets eukaryotic initiation factor 4E-binding protein 1 and phosphorylated ribosomal protein S6 in most cases. Similar results are seen in cases of primary effusion lymphoma and plasma cell myeloma. These findings suggest that activation of Notch1 may be involved in suppression of B-cell-specific gene expression and global loss of the B-cell phenotype in plasmablastic lymphoma, similar to primary effusion lymphoma and plasma cell myeloma. Thus, there might be a role for the Notch1 and mTOR pathways in the pathogenesis and therapy of plasmablastic lymphoma.