Epstein‐Barr virus latent membrane protein‐1 upregulates autophagy and promotes viability in Hodgkin lymphoma: Implications for targeted therapy

Abstract

Hodgkin lymphoma (HL) is composed of neoplastic Hodgkin and Reed-Sternberg cells in an inflammatory background. The neoplastic cells are derived from germinal center B cells that, in most cases, are infected by Epstein-Barr virus (EBV), which may play a role in tumorigenesis. Given that EBV-latent membrane protein 1 (LMP1) regulates autophagy in B cells, we explored the role of autophagy mediated by EBV or LMP1 in HL. We found that EBV-LMP1 transfection in HL cells induced a modest increase in autophagy signals, attenuated starvation-induced autophagic stress, and alleviated autophagy inhibition-or doxorubicin-induced cell death. LMP1 knockdown leads to decreased autophagy LC3 signals. A xenograft mouse model further showed that EBV infection significantly increased expression of the autophagy marker LC3 in HL cells. Clinically, LC3 was expressed in 15% (19/127) of HL samples, but was absent in all cases of nodular lymphocyte-predominant and lymphocyte-rich classic HL cases. Although expression of LC3 was not correlated with EBV status or clinical outcome, autophagic blockade effectively eradicated LMP1-positive HL xenografts with better efficacy than LMP1-negative HL xenografts. Collectively, these results suggest that EBV-LMP1 enhances autophagy and promotes the viability of HL cells.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

High percentages of peripheral blood T-cell activation in childhood Hodgkin's lymphoma are associated with inferior outcome

“…The molecular pathogenesis of HL, which shows a balance of proliferative and apoptotic effects, involves TRAFs, NF-kB, STAT and cytokine pathways, and overexpression of PD-1 with inhibition of caspase activities ( 27 ). Expression of EBV markers, including EBV-LMP or EBER, was a valuable finding in classic patients with HL, where EBV expression is characteristically shown in the HRS cells ( 10 , 28 ). In agreement with those results, our results found that 48.0% cases of HL presented LMP or EBER positivity in biopsy specimens.…”

“…In addition, EBV infection may be involved in pathogenic mechanism of tumorigenesis. Lin et al ( 10 ) reported that LMP1 in HL cells can lead a moderate increase in autophagy signals by increasing expression of the autophagy marker LC3, including reduced autophagic stress and alleviated autophagy inhibition-induced cell death. Marshall et al ( 29 ) suggested that EBV-LMP1 epitopes could induce HL-infiltrating lymphocyte Treg cells.…”

“…The etiology of HL is unknown, but risk factors that have been identified include previous infection with Epstein-Barr virus (EBV), immune system disorders, and exposure to air pollution (10)(11)(12)(13)(14). Rare malignant Hodgkin and Reed-Sternberg (HRS) cells in pathological tissue of HL are encircled by an abundant but ineffective inflammatory cell infiltrate.…”

Activation of MEK1/2/Nrf-2 Signaling Pathway by Epstein-Barr Virus-Latent Membrane Protein 1 Enhances Autophagy and Cisplatin Resistance in T-Cell Lymphoma

“…Later, we observed that depletion of LMP1 effectively reduced the expression of LC3 and Beclin-1, while enhanced that of p62 in lymphoma cells, which hints the possibility of LMP1-mediated chemo-resistance was autophagy-dependent. Likewise, LMP1 also increased autophagic flux of LC3-II and promoted viability in Hodgkin lymphoma cells [ 19 ]. To test our postulation, we delivered 3-MA, an autophagy inhibitor, or rapamycin, an autophagy activator, into lymphoma cells with LMP1 upregulation or downregulation, respectively.…”

EBV and Lymphomagenesis

“…In addition, LMP1 expression plays a role in regulating autophagy. Hodgkin lymphoma cells expressing LMP1 were better able to adapt to starvation-induced autophagic stress [ 127 ].…”