Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma

doi:10.1073/pnas.0408381102

Reactive oxygen signaling and MAPK activation distinguish Epstein–Barr Virus (EBV)-positive versus EBV-negative Burkitt's lymphoma

Departments of ^*Dermatology, ^¶Hematology/Oncology, and ^‡Pathology, Emory University School of Medicine, Atlanta, GA 30322; ^§Department of Microbiology and Immunology, Louisiana State University Health Sciences Center, Shreveport, LA 71130; ^**Cancer Research UK Institute for Cancer Studies, University of Birmingham Medical School, Birmingham B15 2TT, United Kingdom; ^†Division of Adult Oncology, Dana–Farber Cancer Institute, Harvard Medical School, Boston, MA 02115; and ^∥Whitehead Institute for Biomedical Research, Cambridge, MA 02142

Communicated by Douglas C. Wallace, University of California College of Medicine, Irvine, CA, November 11, 2004 (received for review April 19, 2003)

Abstract

Burkitt's lymphoma (BL) is an aggressive B cell neoplasm, which is one of the most common neoplasms of childhood. It is highly widespread in East Africa, where it appears in endemic form associated with Epstein–Barr virus (EBV) infection, and around the world in a sporadic form in which EBV infection is much less common. In addition to being the first human neoplasm to be associated with EBV, BL is associated with a characteristic translocation, in which the Ig promoter is translocated to constitutively activate the c-myc oncogene. Although many BLs respond well to chemotherapy, a significant fraction fails to respond to therapy, leading to death. In this article, we demonstrate that EBV-positive BL expresses high levels of activated mitogen-activated protein kinase and reactive oxygen species (ROS), and that ROS directly regulate NF-κB activation. EBV-negative BLs exhibit activation of phosphoinositol 3-kinase, but do not have elevated levels of ROS. Elevated reactive oxygen may play a role in diverse forms of viral carcinogenesis in humans, including cancers caused by EBV, hepatitis B, C, and human T cell lymphotropic virus. Our findings imply that inhibition of ROS may be useful in the treatment of EBV-induced neoplasia.

angiogenesis

Footnotes

↵ †† To whom correspondence should be addressed at: Emory University School of Medicine, WMB 5309, 1639 Pierce Drive, Atlanta, GA 30322. E-mail: jarbise{at}emory.edu.
Author contributions: T.B., D.F., A.E., and J.L.A. designed research; F.C., T.B., R.L., E.M., C.C., N.M., J.W.S., R.S.W., and J.L.A. performed research; J.W.S., K.S., A.E., and B.S. contributed new reagents/analytic tools; F.C., R.L., D.F., B.S., and J.L.A. analyzed data; and J.L.A. wrote the paper.
Abbreviations: BL, Burkitt's lymphoma; DCF, dichlorofluorescein; EBV, Epstein–Barr virus; MAPK, mitogen-activated protein kinase; ROS, reactive oxygen species.