Molecular Pathological analyses of aberrant expression of the proteintyrosine phosphatase SHP1 gene in terms of lymphomagenesis/leukemogenesis.

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The studies of gene expression on a genomic scale with cDNA microarrays make it easy to measure the transcripts for every gene at once. Various types of lymphomas/leukemias have been analyzed with the cDNA microarray or macroarrays to investigate the molecular basis of lymphomagenesis/leukemogenesis. Recently, our group analyzed the expression pattern of the human NK/T cell line (NK-YS) genome by cDNA macroarray and tissue-microarray comprehensively and systematically followed by RT-PCR and Western blotting. The significant changes in the gene expression of NK-YS cell line were detected : increase in 18 and decrease in 20 genes compared to normal NK cells or peripheral blood mononuclear cells. Among these genes, we found a strong decrease in hematopoietic cell specific protein-tyrosine-phosphatase SHP1 mRNA by cDNA-macroarray and RT-PCR. Further analysis with standard immunohistochemistry and tissue-microarray, which utilized 207 paraffin-embedded specimens of various kinds of malignan … More t lymphomas, showed that 100% of NK/T lymphoma specimens and more than 95% of various types of malignant lymphoma were negative for SHP1 protein expression. The promoter region of the SHP1 gene has been revealed to be highly methylated in patient samples of adult T cell leukemia (methylation frequency 90%), natural killer (NK)/T cell 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 lymphoma cases (100%) than in low grade- MALT lymphoma cases (70%), correlating well with the frequency of no expression of SHP1 protein in high grade- (80%) and low grade-MALT lymphoma (54%). It suggests that the SHP1 gene silencing with aberrant CpG methylation relates to the lymphoma progression in addition to the malignant transformation. Furthermore, the promoter methylation of the SHP1 gene was clearly correlated with the clinical stage such as complete remission or relapse. Loss of heterozygosity with microsatellite markers near the SHP1 gene was showed in 79% of informative ALL cases. These evidences show that the SHP1 gene is a relevant novel biomarker of the wide range of hematopoietic malignancies. Additionally, the loss of SHP1 gene expression is suggested to play an important role in multistep lymphomagenesis/leukemogenesis. Less