MYC overexpression imposes a nonimmunogenic phenotype on Epstein–Barr virus-infected B cells

Staege, Martin S.; Lee, Steven P.; Frisan, Teresa; Mautner, Josef; Scholz, Siegfried; Pajic, Alexander; Rickinson, Alan B.; Masucci, Maria G.; Polack, Axel; Bornkamm, Georg W.

doi:10.1073/pnas.072495599

Cited by 64 publications

(63 citation statements)

References 48 publications

(54 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In all, 34 Myc-repressed genes were represented by this category, and 18 of them were up-regulated >4-fold upon Myc inactivation (Table 1). This was consistent with the observation that Myc overexpression renders B cells nonimmunogenic (26).…”

Section: Resultssupporting

confidence: 80%

See 1 more Smart Citation

Inactivation of Myc in Murine Two-Hit B lymphomas Causes Dormancy with Elevated Levels of Interleukin 10 Receptor and CD20: Implications for Adjuvant Therapies

Dews²,

Park³

et al. 2005

Cancer Research

View full text Add to dashboard Cite

Overexpression of c-Myc and inactivation of p53 are hallmarks of human Burkitt's lymphomas. We had previously showed that transduction of murine p53-null bone marrow cells with a Myc-encoding retrovirus is sufficient for B lymphomagenesis. To address the role of Myc in tumor sustenance, we generated lymphomas induced by the Mycestrogen receptor fusion protein (MycER). Engrafted hosts were continuously treated with the ER ligand 4-hydroxytamoxifen (4-OHT) to allow tumor formation. Subsequent inactivation of MycER via 4-OHT deprivation resulted in tumor stasis but only partial regression. At the cellular level, dormant neoplastic lymphocytes withdrew from mitosis and underwent further B-cell differentiation. Concomitantly, they up-regulated genes involved in lymphocyte proliferation and survival, most notably interleukin 10 receptor A (IL10Ra) and CD20, the target for antibody therapy with Rituxan. We found that overexpression of IL10RA affords significant proliferative advantages and in 4-OHT-deprived animals correlates with eventual tumor relapse. Both dormant and relapsing tumors maintain IL10RA expression suggesting that they might be sensitive to emerging drugs targeting the IL-10 pathway. Upregulation of CD20 following Myc inactivation was also observed in immortalized human lymphocytes. Importantly, in this system, Myc OFF CD20 HIGH cells were more prone to Rituxan-induced apoptosis than Myc ON CD20 MED . Thus, targeting Myc, while moderately effective on its own, shapes the phenotype of dormant neoplastic cells and sensitizes them to adjuvant molecular therapies. (Cancer Res 2005; 65(12): 5454-61)

show abstract

Section: Resultssupporting

confidence: 80%

“…Furthermore, future immunotherapies could use neutralizing antibodies against additional Myc-repressed B-cell differentiation markers identified by us (Mb1, lymphotoxin B, etc.) and by others (24)(25)(26). Such antibodies might be particularly effective in eliminating neoplastic cells that have survived anti-Myc therapies.…”

Section: Discussionmentioning

confidence: 99%

Inactivation of Myc in Murine Two-Hit B lymphomas Causes Dormancy with Elevated Levels of Interleukin 10 Receptor and CD20: Implications for Adjuvant Therapies

Dews²,

Park³

et al. 2005

Cancer Research

View full text Add to dashboard Cite

show abstract

“…41 This nonimmunogenic phenotype is imposed by MYC expression, as it was shown in a conditional model that MYC inactivation results in upregulation of accessory molecules and antigen presentation. 42 However, the mechanism of this MYC-induced repression of immunogenicity was not clear. Our results demonstrate that IKK2/NF-B is controlling expression of several of these such as LFA-1, LFA-3, ICAM-1, TAP1, HLA-I, and HLA-2 (supplemental Table 1).…”

Section: Discussionmentioning

confidence: 99%

The IKK2/NF-κB pathway suppresses MYC-induced lymphomagenesis

Klapproth

Sander

Marinković

et al. 2009

Blood

View full text Add to dashboard Cite

“…Studies of in vitro EBV-transformed cell lines that recapitulate the BL cell phenotype through regulated expression of EBNA2/LMP-1 and c-Myc have shown that overexpression of c-Myc in the absence of LMP-1 is directly responsible for the altered immunogenicity of BL cells (Frisan et al, 1996(Frisan et al, , 1998Staege et al, 2002), which also correlates with alterations of ubiquitindependent proteolysis (Gavioli et al, 2001). BL cells were shown to be resistant to treatment with doses of proteasome inhibitors that are readily toxic for normal lymphoblasts.…”

Section: The Rescue Program: Lmp-2a and The Capture Of Cellular Ubiqumentioning

confidence: 99%

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Masucci

2004

Oncogene

View full text Add to dashboard Cite

Epstein-Barr virus (EBV), a human herpesvirus associated with lymphoid and epithelial cell tumors, encodes several proteins that exploit the ubiquitin-proteasome system to regulate latency and allow the persistence of infected cells in immunocompetent hosts. Further modifications of ubiquitin-dependent proteolysis by activated cellular oncogenes contribute to malignant transformation. A detailed understanding of these processes may lead to the development of new therapeutic strategies for EBVassociated cancers.

show abstract

MYC overexpression imposes a nonimmunogenic phenotype on Epstein–Barr virus-infected B cells

Abstract: Lymphoblastoid cell lines, generated by immortalization of normal B cells by Epstein-Barr virus (EBV)in

Cited by 64 publications

References 48 publications

Inactivation of Myc in Murine Two-Hit B lymphomas Causes Dormancy with Elevated Levels of Interleukin 10 Receptor and CD20: Implications for Adjuvant Therapies

Inactivation of Myc in Murine Two-Hit B lymphomas Causes Dormancy with Elevated Levels of Interleukin 10 Receptor and CD20: Implications for Adjuvant Therapies

The IKK2/NF-κB pathway suppresses MYC-induced lymphomagenesis

Epstein–Barr virus oncogenesis and the ubiquitin–proteasome system

Contact Info

Product

Resources

About