High frequent gene silencing of hemetopoietic cell specific protein tyrosinephosphatase SHP1 in hemetopoietic cell malignancies

The genome-wide studies of gene expression with cDNA microarray make it easy tomeasure the transcription level of most genes at once. Various types oflymphomas/leukemias have been analyzed with the cDNA microarray to investigate themolecular basis of lymphomagenesis/leukemogenesis. Recently, our group analyzed theexpression pattern of the human NK/T cell line (NK-YS, NK-TY2) by cDNA-array andtissue-microarray comprehensively and systematically followed by RT-PCR and Westernblotting. The significant changes in the gene expression of NK-YS and NK-TY2 cell linewere detected: increase in 18 and decrease in 20 genes compared to those of normal NKcells or peripheral blood mononuclear cells. Among these genes, we found a strongdecrease of hematopoietic cell specific protein-tyrosine-phosphatase SHP1 mRNA.Further analysis with standard immunohistochemistry and tissue-microarray, whichutilized 207 paraffin-embedded specimens of various kinds of malignant lymphomas,showed that 100% of NK/T lymphoma specimens and more than 95% of various types ofmalignant lymphoma were negative for SHP1 protein expression. The promoter region ofthe SHP1 gene has been revealed to be highly methylated in patient samples of adult Tcell leukemia/lymphoma (ATLL) (methylation frequency 90%), natural killer (NK)/Tcell lymphoma (91%), diffuse large B-cell lymphoma (93%), MALT lymphoma (82%),mantle cell lymphoma (75%), plasmacytoma (100%) and follicular lymphoma (96%).The methylation frequency was significantly higher in high grade-MALT lymphomacases (100%) than in low grade-MALT lymphoma cases (70%), correlating well with thefrequency of no expression of SHP1 protein in high grade- (80%) and low grade-MALTlymphoma (54%). It suggests that the SHP1 gene silencing with aberrant CpGmethylation relates to the lymphoma progression in addition to the malignanttransformation. Furthermore, the promoter methylation of the SHP1 gene was clearlycorrelated with the clinical stage such as complete remission or relapse. Loss ofheterozygosity with microsatellite markers near the SHP1 gene was showed in 79% ofinformative ALL cases. These evidences show that the SHP1 gene is a relevant novelbiomarker of the wide range of hematopoietic malignancies. Additionally, our resultssuggest that the loss of the SHP1 gene expression plays an important role in multisteplymphomagenesis/leukemogenesis.