Research On Therapy And Prognosis In Extranodal Natural Killer/T Cell Lymphoma And Burkitt Lymphoma

This study mainly focused on the prognosis,target therapy and potential novel biomarker in lympgoma,which is a common type of malignant tumor in China.This contents included two parts:Part 1 Development of new prognostic model based on pretreatment βLRI and LLRI for stage ⅠE/ⅡE upper aerodigestive tract ENKTL,nasal typeExtranodal natural killer/T cell lymphoma(ENKTL)is a rare but highly aggressive non-Hodgkin lymphoma.The treatment outcomes of ENKTL are generally poor,and vary widely.There is no specific prognosis indicators in patients with limited-stage ENKTL.The scoring systems based on both Korean Prognostic Index(KPI)and International Prognostic Index(IPI)should be further modified for ENKTL patients.To identify simple non-invasive prognostic factors for extranodal natural killer/T cell lymphoma(ENKTL),we have investigated the prognostic value of pretreatmentβ2-microglobin to lymphocytes ratio index(βLRI)or lactate dehydrogenase to lymphocytes ratio index(LLRI),by analyzing the retrospective data from 211 ENKTL patients.Receiver operating characteristic(ROC)curve analysis was performed to determine the cut-off value of pretreatment βLRI and LLRI.The univariate analysis indicated that Ann Arbor Stage(p = 0.008),Eastern Cooperative Oncology Group score(ECOG)(p = 0.009),International Prognostic Index(IPI)(p = 0.023),βLRI(p = 0.003),LLRI(p = 0.04),neutrophil-lymphocyte ratio index(p = 0.025)and monocyte/granulocyte to lymphocyte ratio(p = 0.030)were significantly associatedwith overall survival(OS)in ENKTL patients.However,multivariate analysisdemonstrated that only Ann Arbor Stage(p = 0.028),PLRI(p<0.001)and LLRI(p = 0.006)were only correlated independently with OS.Furthermore,βLRI and LLRI based new prognostic model showed improved discrimination for stage IE/IIE upper aerodigestive tract in ENKTL patients than IPI and Korean Prognostic Index.Overall,our study concluded that new βLRI-based prognosis model is useful to stratify ENKTL patients and higher PLRI and LLRI can act as independent prognostic predictor candidates in early stage ENKTL.Part 2 Investigation on antitumor activity of histone deacetylase inhibitor chidamide in BLThe largest prospective multicenter trial for BL reported a 5-year survival rate of 84%for younger patients(<55 years),as opposed to only 62%for elderly patients(>55 years).In particular,elderly patients with comorbidities and patients with endemic BL in developing countries are often not eligible for intensive chemotherapy;therefore,there is a need for novel,targeted therapies.This study assessed the antitumor efficiency and mechanisms of chidamide in BL.Chidamide significantly reduced the viability of BL cell lines.Chidamide promoted cell apoptosis and induced cell cycle arrest.The expression of protein and corresponding phosphorylation in BL cell lines were detected by antibody microarray,which were treated without or with chidamide.GO analysis results showed differentially phosphorylated protein(DPPs)were significantly enriched in biological processes(BP),including response to drug,negative regulation of apoptotic process,regulation of cell proliferation and protein autophosphorylation.For molecular function(MF),DEPs were significantly enriched in protein kinase binding,protein bind,transcription factor binding,enzyme binding and protein tyrosine kinase activity.KEGG pathway analysis demonstrated DPPs were enriched in PI3K-Akt signaling pathway,pathways in cancer,neurotrophin signaling pathway,MAPK signaling pathway and ErbB signaling pathway.The top 5 hub proteins were p53,Bcl2,c-Jun,Src and Myc.Then the results were validated by western blot.It demonstrated that the antitumor efficiency of chidamide is mainly by inhibiting cell proliferation and cell cycle through the PI3K-Akt signaling pathway.P53,Bcl2,Myc,Src and c-jun protein’ play a key role in the antitumor of chidamide.