Functional p53 Signaling in Kaposi's Sarcoma-Associated Herpesvirus Lymphomas: Implications for Therapy

Abstract

The Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) is associated with Kaposi's sarcoma (KS) as well as primary effusion lymphomas (PEL). The expression of viral proteins capable of inactivating the p53 tumor suppressor protein has been implicated in KSHV oncogenesis. However, DNA-damaging drugs such as doxorubicin are clinically efficacious against PEL and KS, suggesting that p53 signaling remains intact despite the presence of KSHV. To investigate the functionality of p53 in PEL, we examined the response of a large number of PEL cell lines to doxorubicin. Two out of seven (29%) PEL cell lines harbored a mutant p53 allele (BCBL-1 and BCP-1) which led to doxorubicin resistance. In contrast, all other PEL containing wild-type p53 showed DNA damage-induced cell cycle arrest, p53 phosphorylation, and p53 target gene activation. These data imply that p53-mediated DNA damage signaling was intact. Supporting this finding, chemical inhibition of p53 signaling in PEL led to doxorubicin resistance, and chemical activation of p53 by the Hdm2 antagonist Nutlin-3 led to unimpaired induction of p53 target genes as well as growth inhibition and apoptosis.

Activation of p53 by MDM2 antagonists has differential apoptotic effects on Epstein–Barr virus (EBV)-positive and EBV-negative Burkitt's lymphoma cells

“…However, it is interesting to note that recent reports on primary effusion lymphoma (PEL) cells treated with nutlin-3 are in line with our results. 13,38 PEL cells are always infected with a transforming human g herpes virus (HHV) called Kaposi's sarcoma herpes virus (KSHV/HHV8) and often co-infected with EBV. 41 These cells, which have a latency I phenotype, as well as EBV(À) PEL cells are very sensitive to nutlin-3-induced apoptosis.…”

“…37 As p53 is rarely mutated in hematologic malignancies, many studies have been carried out on various types of tumor cell, including chronic lymphocytic leukemia B cells (B-CLL), 18,20 myeloma, 14 Kaposi sarcoma herpes virus (KHSV)-induced lymphoma 13,38 and Hodgkin's lymphoma. 19 In some cases, nutlin-3 is also able to induce apoptosis in p53-inactivated cells through a p73-dependent mechanism 39 and, as shown recently in a mantle cell lymphoma cell line carrying mutated p53, to synergize with drugs.…”

Tumor suppressor genes FHIT and WWOX are deleted in primary effusion lymphoma (PEL) cell lines

“…We used cell lines, because they form a renewable resource and have been characterized phenotypically for growth in culture and tumorigenicity in mice, in vitro and in vivo drug susceptibility, mRNA transcription, miRNA expression, p53 status, and other markers (Table 1 and references therein). 3,4,12,13,15 Although the samples displayed a high degree of variability in their genomic signatures, with the use of principle component analysis (PCA) we found that most PEL cell lines (with the exception of JSC1) form a tight cluster. PCA reduced the variability of the data to 3 main and independent components.…”

“…Unlike other lymphomas, no signature translocation or single gene mutation has been associated with PEL to date. The p53 tumor suppressor protein appears functional in PEL cell lines, 15 the Myc locus un-rearranged, although the protein is unusually stable, 16 and no amplifications or deletions are reported for Bcl-2, 2 Bcl-6, 17 Ras, 2 the catalytic subunit of PI3K, 18 phosphatase with tensin homolog or p16/INK4. 18 We therefore used the Affymetrix 6.0 single nucleotide polymorphism (SNP)-based microarray to conduct comparative genomic hybridization (CGH) to look at the global genomic profile of PEL cells.…”

Kaposi sarcoma–associated herpesvirus: immunobiology, oncogenesis, and therapy

“…However, interpreting genetic experiments for LANA is rather complex, since tethering the KSHV plasmids to the host genome is not the only function of LANA. LANA also binds a large number of cellular proteins to modulate their functions, including p53 and many other proteins with specialized functions (120,121). Most recently, cytoplasmic variants of LANA have been described (122), and whole-genome screens have highlighted the importance of LANA during KSHV primary infection (45, 47).…”