Uniform Expression of Notch1, Suppressor of B-Cell Specific Gene Expression, in Plasmablastic Lymphoma
AC Seegmiller, A Maleki, W Kabbani, P Shang, HY Wang, W Chen. UT Southwestern Medical Center, Dallas
Background: While the loss of B-lineage specific gene expression is a distinctive feature of plasmablastic lymphoma (PL), the underlying mechanism remains poorly understood. Notch1 signaling is central for T vs. B-lineage decision in that it promotes T-cell development, while inhibiting B-cell development by interfering with the activity of transcription factors E2A and EBF. In addition, Notch1 signaling also positively regulates the mTOR pathway. In this study, we 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.
Design: Institutional database searches yielded 9 cases of PL with adequate material for further study. Immunophenotypic analyses were performed by both immunohistochemistry (IHC) and flow cytometry (FC). IHC markers included B-cell antigens bcl-2, bcl-6, CD79a, PAX-5, and MUM1, mTOR pathway proteins 4E binding protein-1 (4EBP-1) and phospho-S6-ribosomal protein (pS6), as well as Notch1. IHC for human herpesvirus 8 (HHV8) and in situ hybridization for EBV encoded RNA (EBER) were also performed.
Results: Patients included 6 males and 3 females with a median age of 42 years (range 31-59). Five patients presented with lymph node involvement, 1 with an extramedullary mass, and 3 with primary BM involvement. All were HIV positive except one with post-transplant immunocompromise and all showed evidence of viral infection by either EBV(+) (8/9 cases) or HHV8(+) (1/9 case). All cases were characterized by a diffuse proliferation of medium-sized to large malignant cells with variable plasmablastic morphology. They exhibited almost uniform loss of B-cell associated markers, including CD19 (expressed in 0/9 cases), CD20 (0/9), CD10 (2/9), CD79a (2/9), PAX-5 (1/9), bcl-2 (0/9), bcl-6 (0/9), sIg (2/9), and icIg (3/9). MUM1, required for plasma cell differentiation, was positive in 9/9 cases. Notch1 was expressed in all 9 cases; the pattern was mixed nuclear and cytoplasmic in most cases (6/9), predominantly cytoplasmic in 2 cases, and predominantly nuclear in 1 case. 4EBP-1 and pS6 were detected in a majority of cases (6/7 and 7/7 respectively).
Conclusions: Uniform expression of Notch1 correlated with loss of B-cell markers and activation of the mTOR pathway in PL. This suggests that activation of Notch1 is involved in repression of B-cell specific gene expression and global loss of the B-cell phenotype. Thus, there might be a role for Notch1 and mTOR pathways in the pathogenesis and therapy of PL.
Wednesday, March 11, 2009 9:30 AM
Poster Session V # 168, Wednesday Morning