The Research On The Relationship Between The Methylation Of THBS1 Genes And Pathogenesis Of Acute Myeloid Leukemiaand The Role Of Hypomethylating Agents In Hematopoietic Stem Cell Transplantation

Object:Acute myeloid leukemia threat human health and the incidence include a variety of factors.At present,the relationship between the methylation of gene promoter and acute myeloid leukemia and the role of hypomethylating agents(HMA)in hematological malignant have become more important[1].We have previously found that the level of the Thrombospondin-1 in the serum of acute myeloid leukemia patients was down regulated by protein chip.Thrombospondin-1 is a multifunctional glycoprotein matricellular[2],its coding gene THBS1,is located on human chromosome 15q15,is a potential tumor suppressor gene [3].Some researches show that THBS1 gene promoter hypermethylation inhibit the gene transcription,and there is a significant correlation between promoter hypermethylation and tumorigenesis,for gastric cancer,colon cancer and so on.whether THBS1 gene methylation is related to occurrence in leukemia is still uncertain[4,5].Allogeneic hematopoietic stem cell transplantation(Allo-HSCT)is the only potential trail for patients with acute myeloid leukemia(AML)[6].However,relapse and graft versus host disease(GVHD)remain the main reasons for treatment failure after allo-HSCT.The effect of hypomethylating agents pre-and post-allogeneic hematopoietic stem cell transplantation in acute myeloid leukemia and myelodysplastic syndromepatients has not definite.So we prove a systematic review and meta-analysis of patients with MDS receiving HMA or non-HMA containing IC and best supportive care(BSC)before hematopoietic stem cell transplantation.And the effect of small dose decitabine on early relapse in AML and MDS patients were observed,in order to find therapy methods to improve prognosis and survival after transplantation with AML and MDS patients.Method:1.Human acute myeloid leukemia cell lines HL-60?HL-60/ADM?SKM-1?MV4-11 were cultured.Genomic DNA was extracted from peripheral blood of 30 AML patients and 20 healthy subjects as a control group.The level of the Thrombospondin-1 was observed and methylation-specific polymerase chain reaction(MSP)performed to detect the CpG methylation status.2.Collected the published clinical case-control study data and conference papers for meta-analysis,to evaluate the effect of hypomethylating agents as bridging therapy to hematopoietic stem cell transplantation in patients with myelodysplastic syndromes3.Clinical data of 6 patients have cGVHD effects after allo-HSCT and receive small dose decitabine in our hospital from June 25,2013 to October 27,2015 were collected in this study.Their diagnosis,transplantation method,cGVHD,treatment outcome were retrospectively analyzed.Main results:1.The frequency of aberrant hypermethylation of THBS1 were 36.7%(11/30)in 30 AML patients.But no aberrant methylation of THBS1 genes was found in normal blood.There was great difference between AML patients and normal subjects(P=0.002).In addition,for the human leukemia cell lines HL-60?HL-60/ADM?SKM-1?MV4-11,methylation of THBS1 genes were positive.2.We acquired that compared with IC or BSC pre-transplant,hypomethylating agents as bridging therapy to hematopoietic stem cell transplantation in patients with MDS has higher overall survival(P=0.03)and similar relapse-free survival(RFS)or disease-free survival(DFS).And,it hasn't increased cumulative incidence of relapse(CIR)and nonrelapse mortality(NRM).They has no significant variation in II-IV and III-IV aGVHD.Otherwise,pre-transplant hypomethylating agents can reduce the cGVHD(P=0.03).3.6 patients who received small dose decitabine therapy have decreased effects of c GVHD and have no severe hematologic toxicity,with 1 patients gave up treatment because of pulmonary infection,5 patients were in stable disease stage.Main conclusion:1.The present study showed that,methylation of THBS1 genes occurs in AML patients and human acute myeloid leukemia cell lines.Therefore,the methylation of THBS1 genes may play a role in the initiation of leukemogenesis.2.Hypomethylating agents as bridging therapy to hematopoietic stem cell transplantation can improve the OS and reduce the cGVHD in patients with AML and MDS..3.Small dose decitabine therapy may alleviate the effects of cGVHD after allo-HSCT and improve quality of life.