The Methylation Pattern Of LRP15 Gene In Hematological Diseases

Acute leukemia results from a mutation of DNA within a pluripotential marrow cell or very early progenitor cell. Scientists always forcuse on its pathogenesis and new therapy. Specific roles for methylation have been suggested for a number of important biological processes, including tumorigenesis, differentiation, X chromosome inactivation and imprinting. In most of these cases, methylation has been associated with transcriptional repression of genes. Now methylation is founded to be associated with leukemia and is important for its progress and therapy. To make clear the association of DNA methylation and leukemia, it is necessary to know the methylation pattern of specific gene. LRP15 gene was obtained in our lab, which was methylated in one relapsed leukemia patient. Bioinformatic data show that LRP15 gene may be a tumor associated gene, which may play an important role in pathogenesis and progression of some diseases. In order to identify the association of the LRP15 gene methylation and leukemia, we prospectively analyzed LRP15 gene methylation patterns using methylation-specific polymerase chain reaction (MS-PCR) in patients with adult acute or chronic leukemia and studied the association of methylation patterns with different phases of leukemia and prognostic variables. No deletion of LRP15 gene was detected in all samples. In nearly all French-American-British leukemia subtypes, we found that frequency of LRP15 methylation was 71.23 % ( 52/73 ) of patients with acute leukemia(AL)and no detectable methylation in any of the 9 healthy people. The diffrence in mean methylation for LRP15 among these two kinds of samples was statistically significant (P=0.000). This suggests that the LRP15 gene methylation is a change associated with malignant cells but not with hematopoietic precursors. The assay revealed that LRP15 gene is not methylated in CML patient samples but it is methylated in blast crisis CML patient, which suggests that it may have prognostic significance. The positive rate of LRP15 methylation in AL is higher than that in CML, which suggests that LRP15 gene may have a role in pathogenesis.There are no significant difference between AML and ALL. But hypermethylation of the LRP15 gene was found in 57.14 % ( 16/28 ) of newly diagnosed AL, 76.19%(16/21) of AL in complete remission, 83.33% of relapsed AL respectively. So the LRP15 methylation correlates with a high risk of relapse in patients with AL. Overall survival of patients with LRP15 methylation was shortened among adults with AL. Aberrant LRP15 methylation may have important prognostic implications for clinical monitoring and risk assessment. Our data revealed that LRP15 methylation is a good marker for AL progression and may also play a role in the biology of this malignancy. In conclusion, DNA methylation changes are common abnormalities in leukemia. We also demonstrated for the first time LRP 15 methylation in 5 5. 56% (5/9) adults with benign diseases. Among these patients with LRP 15 gene methylation , four belonged to immune system disease. We confirmed LRP 15 methylation detected in adults with benign hematological diseases by COBRA using both PCR and PCR products sequence analysis. In this benign case, the LRP 15 exon 1 methylation patterns exhibited methylation at all of the CpG dinucleotidesand unmethylation at the same time. It is possible that hypermethylation of this gene is related to the pathogenesis and development of immune system diseases. LRP15 was postulated to be a tumor suppressor gene.