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Role of Double-Stranded RNA-activated Protein Kinase in Human Hematological Malignancies¹

Department of Haematology, Royal Free Hospital School of Medicine, Rowland Hill Street, London NW3 2PF, United Kingdom [S. B., P. P., S. M. H., L-Z. H., A. V. H., K. G.]; and Department of International Clinical Research, Ciba, Basel, Switzerland [A. M.]

The double-stranded RNA (dsRNA)-activated protein kinase (PKR) is one of many genes induced by IFN. The PKR sequentially undergoes autophosphorylation and activation on binding to dsRNA. Previous studies have shown that PKR may be an important factor in the regulation of viral and cellular protein synthesis. Recent studies suggest that PKR may function as a tumor suppressor gene. The role of PKR in various human leukemic cells was therefore investigated. PKR mRNA levels by reverse transcription-PCR, protein expression by Western blot and FACScan analysis, and activity by phosphorylation status were studied. The expression of a known inhibitor of PKR, p58, was also investigated at mRNA and protein levels. A total of 24 samples from normal mononuclear cells (MNCs), 26 samples of acute lymphoblastic leukemia, 26 samples of acute myelogenous leukemia, 32 samples of chronic lymphocytic leukemia, and 5 samples of hairy cell leukemia was investigated. Mean mRNA levels were increased in acute lymphoblastic leukemia and acute myelogenous leukemia and decreased in chronic lymphocytic leukemia compared to normal MNCs. The mRNA levels in hairy cell leukemia were similar to those of normal MNCs. PKR protein was detectable in normal MNCs and leukemic cell extracts, and on FACScan analysis, more than 70% of cells stained positive for PKR. PKR activity was detectable in all samples investigated and was enhanced 4–23-fold in the presence of the synthetic dsRNA, poly(I)·poly(C). Protein expression of a known PKR inhibitor, p58, was barely detectable in normal MNCs and leukemic cells, with high expression in the HeLa cell line. These findings provide no evidence to support the hypothesis that PKR acts as a tumor suppressor in human leukemic cells.

¹ This study was supported by Hoffmann-La Roche, Basel, Switzerland.

² To whom requests for reprints should be addressed. Fax: 0171-794-0645; E-mail: kgguru@rfhsm.ac.uk.

Received 8/12/96. Accepted 1/ 2/97.