Loss of PKR activity in chronic lymphocytic leukemia

• Published in: International journal of cancer Vol. 109; no. 3; pp. 329 - 335
• Main Authors: Hii, Su Ing, Hardy, Lani, Crough, Tania, Payne, Elizabeth J., Grimmett, Karen, Gill, Devinder, McMillan, Nigel A.J.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 10.04.2004; Wiley-Liss
• Subjects: ADP-ribosyl Cyclase - metabolism; ADP-ribosyl Cyclase 1; Aged; Antigens, CD - metabolism; Biological and medical sciences; B‐CLL; Chromosomes, Human, Pair 11 - genetics; Chromosomes, Human, Pair 13 - genetics; Down-Regulation; dsRNA; eIF-2 Kinase - antagonists & inhibitors; eIF-2 Kinase - genetics; eIF-2 Kinase - metabolism; Enzyme Activation - drug effects; Female; Gene Deletion; Hematologic and hematopoietic diseases; HSP40 Heat-Shock Proteins; Humans; interferon; Leukemia, Lymphocytic, Chronic, B-Cell - enzymology; Leukemia, Lymphocytic, Chronic, B-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Membrane Glycoproteins; p58IPK; PACT; Phosphorylation - drug effects; PKR; Poly I-C; Repressor Proteins - pharmacology; RNA, Double-Stranded - metabolism; RNA-Binding Proteins - pharmacology; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - metabolism; Tumors; Human; Chronic; Chronic lymphocytic leukemia; Cancerology; Enzymatic activity; Enzyme; Protein kinase; Lymphoproliferative syndrome; Transferases; Malignant hemopathy
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.11714

There are a number of observations that suggest the dsRNA‐activated protein kinase, PKR, may play an active role in formation and maintenance of leukemia, including nonrandom chromosomal deletions in acute leukemia as well as truncations and deletions of the PKR gene in some leukemia cell lines. However, there is little direct evidence from patient material that this is so. Here we show that full‐length PKR is present but not active in 21 of 28 patient samples from B‐cell chronic lymphocytic leukemia (B‐CLL). PKR from these patients was unable to auto‐activate or phosphorylate substrates but was able to bind dsRNA. Furthermore, the lack of PKR activation was not due to differing levels of the PKR activator, PACT nor of the PKR inhibitor, p58IPK. We compared PKR status with clinical parameters and disease staging. No differences were found between the 2 groups in terms of staging (modified Rai or Binet), age, CD38 status, p53 status, 11q23 deletion status or CEP12 deletion status. However, there was a significant correlation between deletion in 13q14.3 and lack of PKR activity. We show that B‐CLL cells appear to contain a soluble inhibitor of PKR, as lysates from cells lacking PKR activity were able to inhibit exogenous PKR in mixing experiments. Finally, we show suppression of PKR activity was still present following ultrafilitration through a 10,000 Da cutoff filter but was lost upon extraction with phenol/chloroform or by high salt washing. This data suggests loss of PKR activity may contribute to the formation and/or maintenance of CLL. © 2004 Wiley‐Liss, Inc.