Regulation of growth and apoptosis in simian AIDS-associated non-Hodgkin's lymphoma
Description
SIV infection in the rhesus macaque has been intensively studied as a model of AIDS-related non-Hodgkin's lymphoma (ARL). Previous studies show that SAIDS-related non-Hodgkin's lymphoma (sARL) in the rhesus macaque recapitulates the major pathobiologic features of AIDS-NHL. However, beyond infection with RhLCV, little is known about what might be driving the growth and survival of sARL cells. This study investigates the regulation of growth and apoptosis in sARL cells to determine how sARL models human ARL. First, a homolog of KSHV, rhesus rhadinovirus (RRV), was detected by PCR in sARL specimens. Although RRV was detected in nearly 80% of sARL specimens, frequency of virus infection among tumor cells was low. The incidence of RRV infection in PBMC rose with SIV coinfection, but RRV levels did not increase in SIV-infected animals that developed sARL, suggesting that RRV does not have a role in sARL development. This study also analyzes a spontaneous lymphoma in an SIV-negative chimpanzee (Pan troglodytes). Our results eliminate several possible cofactors in the development of this lymphoma, including familiar oncogenic mutations, and infection by chimpanzee-specific rhadinoviruses and lymphocryptoviruses. Finally, to study the influence of positive and negative growth factors in sARL, we used a sARL-derived cell line (LCL8664) that proliferated in response to human IL-6, but was sensitive to growth inhibition by human TGF-beta1. TGF-beta1 inhibited LCL8664 growth by downregulating expression of c-myc, inducing cell cycle arrest and increasing apoptosis. Treatment with IL-6 relieved TGF-beta1-mediated growth inhibition and apoptosis. IL-6 activated STAT3, ERK1/2 MAPK and P13K/Akt, and this activation was reduced by TGF-beta1 treatment. Among Bcl-2 family members, Mcl-1 expression was upregulated by IL-6, partially through the Pl-3K/Akt pathway. The responses of two human ARL-derived cell lines were examined for comparison: 2F7 (AIDS-related Burkitt's lymphoma) and UMCL01-101 (uncharacterized ARL). Like LCL8664, UMCL01-101 showed responsiveness to IL-6, inhibition by TGF-beta1, 2 and partial rescue of TGF-beta1-mediated inhibition by IL-6. Proliferation and protection from apoptosis mediated by IL-6 may provide an important survival signal for ARL cells in vivo , and may provide an important mechanism by which growth suppressive influences (e.g. TGF-beta1) in the tumor environment might be balanced