Epstein-Barr viral DNA in acute large granular lymphocyte (natural killer) leukemic cells.

Serologic studies in a male Caucasian presenting with an acute hepatitis-like illness, associated with an increase in peripheral blood large granular lymphocytes (LGLs), suggested a chronic or reactived Epstein-Barr virus (EBV) infection. The LGL were shown to have a natural killer (NK) cell, CD3- CD16- CD56+ CD57- phenotype and mediated strong nonspecific major histocompatability complex-unrestricted (NK) cytotoxic activity. A progressive increase in the peripheral blood LGL count was associated with a rapid deterioration, hepatic necrosis, and death. Widespread organ infiltration with LGLs suggested a malignant lymphoproliferative condition, but no lymphoid (T-cell receptor or IgH) gene rearrangement or cytogenetic marker was detected. However, molecular analysis identified EBV genomic DNA present in a single episomal form within the LGL, establishing the clonal nature of the LGL proliferation. Confirmation that the EBV had infected the leukemic LGL was obtained by in situ hybridization studies that showed EBV RNA within the LGLs. Immunoblotting of LGL protein extracts established that, of the EBV gene products, EBV nuclear antigen-1 (EBNA-1) was expressed but EBNA-2 and the latent membrane protein (LMP-1) were not detectable in the leukemic cells. These results suggest that EBV may be involved directly in LGL cell transformation, in a manner similar to EBV-associated B-cell lymphomas, although other molecular changes probably contribute to the evolution of a fully malignant leukemic clone.