Clinicopathologic significance of PELI1 expression and its correlation with MYC in malignant lymphoma

Abstract

Background: Overexpression of Myc is known to guarantee a universally aggressive clinical course in B-cell lymphomas. The prototypic mechanism of MYC activation is MYC/IGH rearrangement, however, an alternative mechanism of Myc dysregulation is suspected in cases of Myc high tumors without structural alteration of MYC gene. This study aimed to explore possible link of Myc overexpression and E3 ubiquitin ligase PELI1 which regulates protein activity through post-translational modification. Methods: Immunohistochemistry (IHC) for Myc and PELI1 was performed in a total of 495 cases including B, T or NK-cell and Hodgkin lymphomas, with additional IHC for BCL2, BCL6, CD10, IRF4/MUM1, CD5, CyclinD1, Ki-67 and Myc in diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma (MCL). Flourescence in situ hybridization (FISH) for MYC rearrangemnt and MYC amplification was performed in DLBCL and MCL cases. Immunohistochemical expression of PELI1 was confirmed with western blot and real time RT-PCR in 14 malignant lymphoma cell lines. Results: High expression of Myc or PELI1 was found in high grade B-cell lymphoma cases such as DLBCL, Burkitt lymphoma and plasmablastic lymphoma, whereas low grade B-cell lymphoma, T / NK-cell lymphoma and Hodgkin lymphoma cases showed very low level of expression. The IHC results of PELI1 were concordant with in vitro cell line studies

RL7, Pfeiffer, SUDHL-2, DOHH2 and Ramos cell lines showed high levels of PELI1 protein and also mRNA. In DLBCL, PELI1 expression was positively correlated with expression of Myc, BCL6, BCL2 (all p≤0.001) and IRF4/MUM1 (p=0.066). In DLBCL, high expression of PELI1 was associated with frequent bone marrow involvement (p=0.013) and shorter disease-free survival (p=0.002). In MCL, high Myc expression was significantly frequent in blastoid/pleomorphic variants and was associated with shortened overall survival and disease-free survival by univariable and multivariable analyses (all P < 0.05). Conclusions: These results suggest that PELI1 might participate in the pathogenesis of aggressive B-cell lymphomas, in collaboration with Myc. Overexpression of Myc or PELI1 can predict inferior outcome in patients with DLBCL or MCL.