Study Of Aberrant Epigenetic Alterations In A Chinese AML Pedigree With A MLL3 Mutation And Cochrane Systematic Reviews For Efficiency And Safty Of High Doses Of Daunorubicin For Treating AML

PART 1 Study of aberrant epigenetic alterations in a Chinese AML pedigree with a MLL3 mutationSection 1 Study of aberrant DNA methylation in a Chinese AML pedigree with a MLL3 mutationBackground and Objective:Many studies indicate that abnormal epigenetic programming plays a major pathogenic role in cancer. Aberrant DNA methylation which is one kind of important Iepigenetic alteration,is concerned with many cancers including acute myeloid leukemia and colorectal carcinoma. In our previous study, we found a germline mixed lineage leukemia 3(MLL3) stop codon mutation in a Chinese pedigree. We decided to pursue our study to explore pathogenesis and progression in this cancer pedigree.Also we hope to demonstrate the relationship between DNA methylation and cancer.Materials and Methods: We selected a Chinese cancer pedigree and colected bone marrow or peripheral blood from 2 colorectal carcinoma (CRC) patients, 2 acute myeloid leukemia (AML) patients, and 1 normal control donor without MLL3 gene mutations. We examined the genome-wide DNA methylation level of cases and explored the role of methylation in pathogenesis and progression. Genome-wide DNA methylation level was measured using the Infinium HumanMethylation450 BeadChip.Results:DNA methylation status in the four cases, who all harbor a MLL3 germline mutation,differed from that of the normal control, and hypermethylation was more prevalent. Also,more CpG sites were hypermethylated in the acute-phase AML patient than in the AML patient in remission. Fifty-nine hyper- or hypomethylated genes were identified as common to all four cases. Genome-wide DNA methylation analysis demonstrated that differentially methylated sites among AML and CRC cases and the control were in both promoters (CpG island) and gene body regions (shelf/shore areas). Hypermethylation was more prevalent in cancer cases.Conclusions:The study supports the suggestion that pathogenesis in this cancer pedigree is association with aberrant DNA methylation and high level of DNA methylation plays a role in disease pathogenesis and progression.Section 2 Study of a unique histone H3K4me3 genome binding pattern identified in a Chinese AML pedigree with a MLL3 mutationBackground and Objective: Evidence suggests that alterations in histone modifications are crucial in cancer development and progression. Among these, histone 3 lysine 4 trimethylation (H3K4me3) which is one of the most common histone modifications, is found in promoters of active genes and is proposed to promote gene expression. Aberrant H3K4 methylation is association with cancer. In our previous study,we found a germline MLL3 stop codon mutation in a Chinese pedigree. MLL3 proteins act as methyltransferase and regulate H3K4 methylation. Our study aims to evaluate the H3K4me3 genome binding pattern in this cancer pedigree with MLL3 mutation and have further understanding about pathogenesis in this pedigree. Also we hope to find valuable epigenetic marker of cancer.Materials and Methods: To eamong 3 cancer patients in a Chinese pedigree with a heterozygous stop codon mutation in MLL3 (coding a histone H3K4me3 methyltransferase)segregating with colorectal carcinoma (CRC) and acute myeloid leukemia (AML) and a mutation-free normal control, ChIP-chip analyses were performed to determine which promoters coprecipitated with the H3K4me3 antibody in both patients and control. The pulled-down genes were mapped to Kyoto Encyclopedia Of Genes And Genomes (KEGG)pathways.Results:Although the number of identified genes was not significantly differ between patients and control, we found an unique profile of H3K4me3 in AML and CRC patients compared with control that the identified genes were concentrated in the carcinogenesis-associated pathways.Conclusions:Our results suggested that pathogenesis in this cancer pedigree is association with unique H3K4me3 binding pattern and genome-wide H3K4me3 profiles may be useful as a hallmark of cancer.PART 2 Cochrane systematic reviews for efficiency and safty of high doses of daunorubicin for treating AMLBackground and Objective: The right dose of daunorubicin (DNR) for the treatment of newly diagnosed acute myeloid leukemia (AML) is uncertain. Systematic review for efficacy and safety about high dose of daunorubicin (HD-DNR) compared with traditional low dose of daunorubicin (LD-DNR) and idarubicin (IDA) during induction therapy of newly diagnosed acute myeloid leukemia.Materials and Methods: We compared the efficacy and safety of HD-DNR and LD-DNR or IDA during induction therapy of newly diagnosed AML. Data of 3,824 patients from 1,796 articles in the literature were retrieved and six randomized controlled trials were analyzed. The primary outcomes were overall survival (OS), disease-free survival (DFS),and event-free survival (EFS). The secondary outcomes included complete remission (CR),relapse, and toxicity.Results:The meta-analysis results suggest that comparing HD-DNR with LD-DNR, there were significant differences in CR(relative risk(RR)= 1.19,95%confidence interval(CI)[ 1.12, 1.18] ,p<0.00001),OS(hazard ratio(HR)=0.88, 95%CI[0.79,0.99], p=0.002), and EFS (HR=0.86,95%CI [0.74, 1.00], p=0.008), but not in DFS, relapse, and toxicity. There were no statistically significant differences in any other outcomes between HD-DNR and IDA.Conclusions:The analysis indicates that compared with LD-DNR, HD-DNR can significantly improve CR, OS and EFS but not DFS, and did not increase occurrence of relapse and toxicity.