Epigenetic abnormalities, such as aberrant DNA hyper-methylation of CpG islands, have been revealed to be inherited over cell divisions and play important roles in lymphomagenesis/leukemogenesis. We identified the SHP1 gene of which expression was specifically down regulated in hematopoietic malignancies by DNA-macroarray, followed by confirmation with RT-PCR and tissue microarray. With methylation specific PCR (MSP), bisulfite sequencing and restriction enzyme-mediated PCR analyses, aberrant methylation in the CpG island of the SHP1 gene was detected in many leukemia/lymphoma cell lines as well as in patient specimens, including DLBCL (methylation frequency 93%), MALT lymphoma (82%), MCL (75%), plasmacytoma (100%) and follicular lymphoma(96%). Additionally, the SHP1gene methylation was clearly correlated with the clinical stage, suggesting that the SHP1 gene silencing with aberrant CpG hyper-methylation relates to the lymphoma progression.
We analyzed the methylation status among PBMCs from healthy volunteers, HTLV-I carriers, smoldering ATLL and acute ATLL patients. We found the significant correlation between the presence of CpG island methylator phenotype (CIMP) and the progression of adult T-cell leukemia/lymphoma (ATLL), suggesting that systemic aberrant DNA hyper-methylation of specific target genes induces and/or promotes the onset and progression of ATLL.
In order to examine whether H.pylori infection could induce CIMP and could involve in the tumor development and progression, we investigated gastric MALT lymphomas and gastric diffuse large B-cell lymphomas (DLBCL) cases with/without H.pylori infection and remission cases. The mean score of CpG islands hyper-methylation in gastric MALT lymphomas was 3.5. After the H. pylori eradication therapy, the score significantly decreased to 2.9 in early state of eradication therapy, and became very low value (0.9) in remission cases. Furthermore, in the cases of MALT lymphoma with DLBCL showed high methylation score 4.4 and DLBCL showed 5.6. These results indicate that the CpG island hyper-methylation score significantly increased in accordance with the progression from low grade to high grade lymphomas with H. pylori infection. Additionally, H. pylori infection was suggested to induce the aberrant DNA hyper-methylation and CIMP phenotype in gastric MALT lymphomas.
Present evidences strongly suggest that the gene silencing associated with epigenetic abnormalities is playing a key role to induce onset and progression of lymphomas/leukemias. Furthermore, DNA hyper-methylation profiles of specific genes in addition to CIMP phenotype and the score of methylated genes are suggested to be sensitive markers of onset and progression of lymphomas/leukemias.
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA