The Methylation Pattern Of ZO-1 Gene In Myelodysplastic Syndrome

Several genes are silenced in MDS because of abnomal methylation status of their promoter. In the proceeding of this malignancy diease, some genes which control cell cycle and differentiation are lost in part of the paraplasmic clong cells. Professor Yu Li found that a specific gene ZO-1 maybe an important gene in hematological malignances. Abnomal methylation status of ZO-1 gene promoter may play an important role in pathogenesis and progression of hematological malignances. ZO-1 protein is a member of membrane-associated guanylate kinase homologs (MAGUK). It is a key factor of tight junction and cell proliferation and differentiation. The expression of ZO-1 may associate with tumor differentiation and cancer progression. We found that the promoter region of ZO-1 gene is hypermethylation, which expression silence in acute leukemia cell line. ZO-1 gene may be associated with pathogenesis and progression of acute leukemia. ZO-1 may be a tumor suppressor in hematological malignances.The objective was to investigate the methylation status of ZO-1 gene in Myelodysplastic syndrome (MDS) and identify its roles in diagnosis of MDS. We detected the methylation status of CpG sites of ZO-1 gene in HL60 cell line, a MDS patient and a health donor using bisulfite sequencing. (1) The positive rate of CpG sites of HL60 is 96.74%. (2) The positive rate of CpG sites of health people is 0.93%. They show that the CpG Island in the 5' regulatory regions of ZO-1 gene is unmethylated. (3) The positive rate of CpG sites of the MDS patient is 6.51%. We can infer that the CpG island methylation in the 5' regulatory regions of ZO-1 gene is abnormal. (4) The distinction between health people and MDS patient is statistically significant (P < 0.05). It suggests that Aberrant ZO-1 gene methylation may have important role in pathogenesis of MDS. Then we prospectively analyzed ZO-1 gene methylation patterns using methylation-specific polymerase chain reaction (MS-PCR) in health people, MDS patients and patients with benign hematological diseases. No ZO-1 promoter methylation was detected in healthy people and patients with benign hematological diseases. Our data reveal that there is no association between hypermethylation patterns of ZO-1 gene and pathogenesis of benign hematological diseases. So the ZO-1 gene methylation state has no correlationship with immune disorder. 56.5 %( 48/85) MDS patients were found that ZO-1 gene promoter of their bone marrow was methylation. The positive rate of ZO-1 methylation in MDS is higher than that in healthy people and patients with benign hematological diseases, which is statistically significant (P < 0.05). The methylation status of ZO-1 gene promoter in the subtypes of MDS as follow: RA (18/37, 48.6%), RAS (4/6, 67%), RCMD (19/30, 63%), RAEB (7/12, 58%). Every subtype of MDS patients had statistically distinction from healthy people and patients with benign hematological diseases (P < 0.05). It suggests that ZO-1 plays an important role in pathogenesis of MDS. And it is a suppressive gene against hemotological malignancy. In MDS patient bone marrow, ZO-1 promoter has a hypermethylation state, which is a specialty in MDS. The ZO-1 gene acts as a gene marker helpful in MDS diagnosis. In conclusion, aberrant ZO-1 gene methylation patterns may have association with pathogenesis and progression of MDS. Maybe, ZO-1 gene is a potential related gene in malignancy hematological diseases. ZO-1 was postulated to be a target for diagnose and treatment.