Dysregulated MYC Expression in Aggressive Mantle Cell Lymphomas
Michael J Kluk, Papiya Sinha, Paola Dal Cin, Scott J Rodig. Brigham and Women's Hospital, Boston, MA
Background: The cell cycle regulators MYC (c-MYC) and cyclin D1 are well-recognized oncoproteins in B-cell lymphomas. Nearly all Burkitt lymphomas (BL) and a subset of diffuse large B-cell lymphomas (DLBCL) exhibit elevated MYC protein expression due to transcriptional deregulation following a balanced translocation involving MYC and, most commonly, the immunoglobulin heavy chain locus (IgH). In contrast, most mantle cell lymphomas (MCL) exhibit elevated cyclin D1 expression due to rearrangement between Cyclin D1 (CCND1) and IgH. Interestingly, the presence of a MYC rearrangement and/or gains of the MYC locus have been reported in rare cases of MCL and may be associated with a more aggressive course. Our objective was to improve our understanding of pathological features of MYC+ MCL by directly assessing MYC protein expression using immunohistochemical detection.
Design: Immunohistochemistry (IHC) for MYC using a rabbit monoclonal antibody was performed on 5um formalin fixed paraffin embedded tissue sections from reactive tonsil, BL, MYC translocation positive-DLBCL and 28 cases of MCL using the Ventana Benchmark platform. The percentage of nuclei positive for MYC was scored by two pathologists and the results were correlated with the morphologic subtype, Ki67 proliferation fraction and genetic status.
Results: Nuclear MYC expression was detected in approximately 10% of lymphocytes in tonsillar tissue, but was detected in >50% tumor nuclei in all cases of BL and MYC translocation positive-DLBCL. Among all MCL cases tested, a majority (22/28 cases, 79%) demonstrated a low MYC score (≤50% tumor nuclei positive, range: 5-50%). However for a minority of cases (6/28 cases, 21%), we observed a high MYC score comparable to that seen for MYC translocation positive-DLBCL and BL (>50% tumor nuclei positive, range: 60-80%). All cases of MCL with a high MYC score had a high Ki67 proliferation index. In addition, a high MYC score corresponded with a morphologic diagnosis of an aggressive variant of mantle cell lymphoma (eg, blastoid or pleomorphic) in 5/6 cases. Interestingly, the increased MYC expression observed in a subset of MCL was not uniformly associated with an underlying MYC translocation.
Conclusions: Increased MYC protein expression, comparable to that observed in MYC translocation positive-DLBCL and BL, is characteristic of a subset of aggressive MCL. However, dysregulated MYC expression in MCL can occur independently of the typical balanced translocations observed for BL and MYC+ DLBCL. These results suggest that dysregulated MYC expression contributes to the development of a subset of aggressive MCL.
Monday, March 19, 2012 1:00 PM
Poster Session II # 195, Monday Afternoon