HIV Implicated in the cis-Activation of c-fes in a Subset of HIV-Associated Lymphomas

K. MACK¹, R. WEI², B. HERNDIER², B. SHIRAMIZU², N. ABBEY², R. GASCON², A. ELBAGGARI², M. HURT², T. EARNST³, and M. MCGRATH². ¹SLIL Biomed. Corp., Menlo Park, CA; ²Univ. of California, San Francisco Gen. Hosp., CA; and ³Harvard Med. Sch., Boston, MA

Clonal HIV insertions upstream of the proto-oncogene c-fes were identified in a subset of AIDS-associated high-grade non-Hodgkin's lymphomas.  These lymphomas included large cell lymphomas interspersed with prominent macrophages and a T-cell lymphoma.  In a representative case of these neoplasias, tumor associated macrophages were characterized and found to co-express the proto-oncogene c-fes and HIV p24.  The c-fes gene product, p93-c-fes was found in an activated, phosphorylated state in macrophages isolated from this tumor tissue.  An HIV promoter insertion model characterized 3'LTR mediated cis-activated expression through the c-fes upstream genomic region in the human Jurkat T-cell line, K562 myeloid progenitor cell line, and primary cultured human macrophages.  The cotransfection of a c-fes cDNA enhanced 3'LTR cis-activation through the c-fes upstream genomic region indicating the possible presence of a positive feedback mechanism that potentiates gene dysregulation. This study presents further evidence for tumor-associated retroviral-mediated insertional mutagenesis at a specific genomic locus in humans that may play a direct role in lymphomagenesis.

Key Words: c-fes, Lymphoma

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