Activation of the p53 Pathway Defeats Aggressive Viral Lymphoma

Cancer researchers working with a mouse model have shown that reactivation of the p53 pathway was effective in treating an aggressive lymphoma caused by infection with Kaposi's sarcoma herpes virus (KSHV).

KSHV is a human tumor virus that causes Kaposi's sarcoma and primary effusion lymphoma (PEL). PELs are aggressive lymphomas with reported median survival time less than six months after diagnosis. There are no current therapies effective against the aggressive, KSHV-induced PEL.

The TP53 gene encodes a transcription factor (p53) that plays a central role in protecting cells from tumor development by inducing cell-cycle arrest or apoptosis via a complex signal transduction network referred to as the p53 pathway. The TP53 gene is mutated or deleted in 50% of all malignant tumors.

In a paper published in the April 2, 2007, issue of the Journal of Clinical Investigation, investigators at the University of Helsinki (Finland) described the use of the protein Nutlin-3a to prevent the suppression of p53 tumor-inhibitor protein caused by the binding of that protein to KSHV latency-associated nuclear antigen (LANA) and to murine double minute 2 (MDM2). Nutlin-3a disrupted the p53-MDM2-LANA complex and selectively induced massive apoptosis in PEL cells. In the mouse model, Nutlin-3a had striking anti-tumor activity, protecting animals that had received transplants of human PEL cells.

The researchers wrote that, "Our results therefore present new options for exploiting reactivation of p53 as what we believe to be a novel and highly selective treatment modality for this virally induced lymphoma.”


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