Identifying Biomarkers For CML Development And Therapeutic Effect Based On DNB Theory

Chronic myeloid leukemia(CML)is a malignant tumor formed by the proliferation of bone marrow hematopoietic stem cells.Its incidence is increasing year by year.In recent years,some biomarkers of CML have been found in research at home and abroad,which play an important role in cancer diagnosis,prognosis and treatment decision making.But so far,the patient’s condition has not been completely cured.Gene expression data is used to screen biomarkers is one of the main approaches to research biomarkers in recent years.In this study,the gene expression datas of CML in each development stage and treatment are used to analysis systematically,based on the dynamic network biomarkers(DNB)theory to identify the relevant biomarkers in each process of CML.Based on the competitive endogenous RNA(ceRNA)theory,the dysregulated lncRNA-associated ceRNA network(DLCN)are constructed for the three phases of chronic phase(CP),accelerated phase(AP)and blastic crisis(BC)of CML.And the biomarkers for CML development are identified by DNB theory.In addition,based on the gene expression data of CML patients treated with imatinib at each time point,this paper provides a therapeutic effect recognition strategy which is used to monitor the therapeutic effect of diseases based on DNB theory.According to DNB criteria,therapeutic effect criteria is constructed,and therapeutic effect index(TEI)is established to detect the time point of pre-stable state and identify biomarkers.The main work of this thesis is as follows:(1)Hematopoietic stem cells(HSCs)gene expression dataset of CML patients in CP,AP and BC is selected.The probe set is re-annotated to obtain the corresponding lncRNA and mRNA expression profile data,and the significant differences expressed(SDE)genes are screened.The experimentally validated miRNA-mRNA interactions are downloaded from Tar Base v8.0 database and starBase v2.0 database,and the experimentally validated miRNA-lncRNA interactions are downloaded from starBase v2.0 database.By integrating the mutual regulation between lncRNA,miRNA and mRNA with the SDE gene expression profile data,the DLCN of CP,AP,and BC for CML are constructed.Based on DNB theory,the ceRNA network modules are identified and biomarkers related to the three stages of CML are obtained.At the same time,the critical index for detecting disease outbreaks are constructed to enhance the effectiveness of the results.The effect of biomarkers in CML is verified by KEGG enrichment analysis and literature mining.From the perspective of ceRNA,the understanding of CML pathology is deepened.The identification of biomarkers for CML development help discover the effective biomarkers of CP,AP and BC for CML in the future,so as to help patients get timely treatment,control the development of the disease,and reduce the mortality of CML.(2)Three gene expression datasets treated with imatinib for CML are selected.The original CEL files are normalized.And the batch effect is adjusted.Comparing the normal samples with the CML samples,SDE genes are selected.SDE genes are clustered by hierarchical clustering.According to DNB theory,therapeutic effect criteria is constructed,and the gene markers related to therapeutic effect of CML are identified.TEI is established to observe the dynamic change of treatment effect,which is used to predict and determine when the condition is in the pre-stable state.At the same time,the probe set is re-annotated to obtain the corresponding lncRNA and mRNA expression profile data,and the significant differences expressed(SDE)genes are screened.By integrating the mutual regulation between lncRNA,miRNA and mRNA with the SDE gene expression profile data.From the perspective of ceRNA,DLCN of CML treated with imatinib for 1 month is constructed.Based on therapeutic effect criteria,the ceRNA network module is identified,lncRNA and mRNA markers related to therapeutic effect of CML are obtained.By identifying the significantly enriched KEGG pathway of mRNA in the ceRNA module,the function of lncRNA is analyzed.The identification of biomarkers for therapeutic effect help to timely treat patients,reduce drug resistance,prevent treatment failure and recurrence,and significantly reduce the mortality rate of CML.By comparing the biomarkers for development of CML in(1)with the biomarkers for therapeutic effect of CML in(2),it’s found that SGMS1 exists simultaneously in CP,BC and therapeutic effect of CML.This important discovery will help to promote the research of new therapeutic targets for CML,and provide certain theoretical direction and theoretical basis for researchers.