Lack of phosphotyrosine phosphatase SHP-1 expression in malignant T-cell lymphoma cells results from methylation of the SHP-1 promoter

SHP-1 is an important negative regulator of signaling by several receptors including receptors for interleukin-2 (IL-2R) and other cytokines, SHP-1 ac ts by dephosphorylating the receptors and receptor-associated kinases such as IL-2R-associated Jak3 kinase. We found that SHP-1 protein was not detect able or greatly diminished in most (six of seven) T cell. lines derived fro m various types of T cell lymphomas and all (eight of eight) cutaneous T-ce ll lymphoma tissues with a transformed, large-cell morphology, All T-cell l ymphoma lines tested (eight of eight) expressed diminished amounts or no de tectable SHP-1 mRNA. These T cell lines did not, however, carry any mutatio ns in the SHP-1 gene-coding, splice-junction, and promoter regions. Importa ntly, SHP-1 DNA promoter region fn the T cell lines was resistant to digest ion with three different methylation-sensitive restriction enzymes. This re sistance was reversed by treatment of the cells with a demethylating agent, 5-deoxyazacytidine. The treatment resulted also in the expression of SHP-1 mRNA and, less frequently, SHP-1 protein. The expression of SHP-1 protein was associated with dephosphorylation of the Jak3 kinase. These results sho w that lack of SHP-1 expression is frequent in malignant T cells and result s from methylation of the SHP-1 gene promoter. Furthermore, they indicate t hat SHP-1 loss may play a role in the pathogenesis of T cell lymphomas by p ermitting persistence of signals generated by IL-2R and, possibly, other re ceptor complexes.