Constitutive expression of cytotoxic proteases and down-regulation of protease inhibitors in LGL leukemia.
Large granular lymphocyte (LGL) leukemia is a lymphoproliferative disorder often associated with rheumatoid arthritis. The etiology of LGL leukemia is not known. In order to better understand the pathogenesis of LGL leukemia, we analyzed differential gene expression using microarray technology. We found that approximately 80 genes were up-regulated and 12 genes were down-regulated when compared to normal peripheral blood mononuclear cells (PBMC). In the present study, we were interested in a group of genes involved in cytotoxic function. The up-regulated genes involved in cytotoxic function were serine proteinases (granzymes A, B, H and K) cysteine proteinases [cathepsin C, cathepsin W (lymphopain)], calpain small subunit and caspase-8. In addition, a pore-forming protein perforin, was also up-regulated. Northern blot analysis and RNase protection assays (RPA) confirmed that these genes were over-expressed in the majority of samples from LGL leukemia patients. Of interest, proteolytic inhibitors such as cystatin C, A, alpha-1 antitrypsin and metalloproteinase inhibitors were down-regulated in leukemic LGL when compared to normal peripheral blood mononuclear cells. Importantly, the pattern of gene expression in leukemic LGL resembles that seen in activated cytotoxic T cells (CTL).
Kothapalli
Ravi
R
H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. kothapar@moffitt.usf.edu
Bailey
Ratna D
RD
Kusmartseva
Irina
I
Mane
Shrikant
S
Epling-Burnette
P K
PK
Loughran
Thomas P
TP
D020789:Cathepsin C / Q000235:genetics; D056664:Cathepsin W; D002403:Cathepsins / Q000235:genetics; D055316:Cystatin C; D015891:Cystatins / Q000235:genetics*; D003546:Cysteine Endopeptidases / Q000235:genetics; D015536:Down-Regulation; D010450:Endopeptidases / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic; D053804:Granzymes; D006801:Humans; D007945:Leukemia, Lymphoid / Q000201:enzymology / Q000235:genetics / Q000276:immunology*; D012697:Serine Endopeptidases / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
C525030:CST3 protein, human; D055316:Cystatin C; D015891:Cystatins; D002403:Cathepsins; D010450:Endopeptidases; D020789:Cathepsin C; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human; C534187:CTSW protein, human; D056664:Cathepsin W; D003546:Cysteine Endopeptidases