The Expression Of Histone Deacetylases 1 In DLBCL And Its Prognostic Significance

Objectives:Diffuse large B-cell lymphoma(DLBCL),a clinically and biologically heterogeneous tumor,is the most common subtype of malignant lymphoma,representing 20?30%of all lymphoproliferative disorders.Although 50?70%of the patients with DLBCL can be cured by current standard treatment with rituximab-based chemotherapy(R-CHOP),about 50%of the patients are found to be inadequate by this treatment,in which 20%of patients suffer from primary refractory and others relapse after achieving complete remission.Recently,deeper understand of molecular characteristic of lymphoma will help us to develop novel target therapy for DLBCL treatment.It is reported that there is an activated histone deacetylases(HDAC)that may contribute to the development of lymphoma.However,the expression of HD AC 1 and its clinical significance in DLBCL was still unclear.In this study,we investigate the expression of HD AC 1 in tumor cells of DLBCL and the relationship between HDAC1 expression and clinical characteristic of the patients.Moreover,we study the effect of HDACl inhibitor on cell proliferation,cell cycle,and apoptosis in DLBCL.Methods:Total 55 cases(below 60 years)with newly diagnosed DLBCL during Feb 2007 to March 2009 in The First Affiliated Hospital of Zhejiang University were reviewed and analyzed.HDACl expression in tumors was analyzed by immunohistochemical(IHC)staining.Furthermore,the level of HDACs in three kinds of DLBCL cell lines was detected using real-time PCR.The effect of selective HDAC inhibitor sodium valproate(VPA)on cell proliferation,cell cycle,and apoptosis was determined using a CCK8 assay,flow cytometry,and Western blotting analysis.Results:High HDACl expression was detected in 85.4%(47/55)cases.The 5-year overall survival(OS)and progression free survival(PFS)of all patients with DLBCL were 50.9%and 45.5%,respectively.There is no relationship between HDACl expression and B symptoms,elevated lactic dehydrogenase(LDH),performance status(ECOG),NCCN international prognostic index score,tumor involvement,subtype and treatment response.For the patients with low HDAC1 expression,the 5-year OS was 100%,which was significantly higher than cases of high expression of HDACl(42.6%,p=0.009).The 5-year PFS for low expression or high expression group was 75%and 40.4%,respectively(p=0.051).Moreover,the level of HDACs mRNA in all tested DLBCL cell lines was detected.The data showed that high expression of seven kinds of HDACs was observed in GCB subtype cell line Su-DHL-16,weak expression was observed in non-GCB subtype cell line Farage.However,negative expression of HDACs was found in OCI-LY3.Furthermore,VPA inhibited cell proliferation in dose-and time-dependent manner,resulted in cell cycle arrest,and activation of caspase-3.Conclusion:Majority of young patients with DLBCL expressed HD AC1.The patients with low expression had better OS and PFS than those with high HDAC1 expression.Expression of HDAC1,HDAC2,and HDAC9 in GCB subtype cell line was higher than that of non-GCB subtype cell lines.Treatment with selective HDAC1 inhibitor VPA inhibited cell proliferation,and resulted in cell cycle arrest and activation of caspase-3.Taken together,high expression of HDAC1 was related to prognosis of DLBCL patients,suggesting that targeting HDAC1 is a novel approach for DLBCL treatment.