Histone Modification Alterations:Mechanism Of Malignant B-cell Progression And Targeted Therapy

Background: Cardiac side effects of doxorubicin have limited its clinical application.The aim of this study was to explore new Dox-loaded dextran-based nano-carriers(NCs)in efficiently targeting tumor growth with less cardiac toxicity.Methods: We developed Dox-loaded NCs which displayed a 2-fold release ratio of Dox in the mimic tumor site condition(p H 5.0 with 10 m M glutathione,GSH)as much as that in systemic circulation condition(p H 7.4).Results: Lymphoma cells treated with Dox-NCs had significantly higher intracellular Dox concentrations and more apoptotic induction,with lower P-gp expression,when compared with those treated with Dox alone.The identified mechanism of action,apoptosis,was triggered through survivin reduction and caspase-3 activation.Even in the Dox-resistant cells,Dox-NCs could significantly inhibit cell growth and induce apoptosis.In murine lymphoma xenograft models,Dox-NCs also remarkably significantly retarded tumor growth,assessed by murine weight,and demonstrated less cytotoxicity.Noticeably,apoptotic myocardial cells were decreased in the Dox-NCs-treated group,when compared with the control group,which was consistent with low intracellular Dox concentration in the cardiac cell line H9C2.Conclusion: Dox-NCs showed an anti-lymphoma effect with reduced cardiac toxicity in both in vivo and in vitro models,could be a potential therapeutic agent in the treatment of lymphoma.Background: Diffuse large B-cell lymphoma(DLBCL)represents the most common neoplastic disorder of B-lymphocytes.In our clinical trial(NCT02753647),we found that chidamide,a histone deacetylase inhibitor,plus R-CHOP elicits favorable outcome,including DLBCL patients with double BCL-2/MYC expression.Therefore,we aim to investigate the underlying mechanism.Methods: Tumor samples of DLBCL patients were transplanted into immunodecient(NOD-SCID)mice to establish patient-derived xenograft(PDX)models.The dose and administration schedule were as follows: doxorubicin 0.6 mg/kg twice a week,chidamide12.5 mg/kg/day for two weeks.ATAC-seq and RNA-seq were performed to achieve an integrative transcriptomic and epigenomic analysis of PDX models on Day 7 and Day 14 of treatment.Results: We observed significant growth inhibition of xenografted tumors treated with chidamide and doxorubicin.ATAC-seq revealed that chidamide and doxorubicin co-repress distal cis-regulatory elements(i.e.enhancers)affecting differential binding of CTCF,BORIS and B-lymphocyte differentiation related transcription factors,repressing chromatin accessibility of MYC.RNA-seq revealed that chidamide and doxorubicin synergistically regulate multiple signaling transduction pathways,including JAK-STAT,NOTCH,PI3 K and BCR signaling pathways.Conclusions: Chidamide can synergize with doxorubicin to remodel the landscape of accessible chromatins in lymphoma cells,regulate multiple signaling transduction pathways thus inhibit the growth of DLBCL.Background:Diffuse large B cell lymphoma(DLBCL)is the most common subtype of non-Hodgkin lymphoma and represents a heterogeneous disease with variable clinical course.Myeloid-derived suppressor cells(MDSC)have been demonstratedas a key negative immune regulator of cancer.However,the detailed mechanism of alterations in MDSCs in DLBCL was not well elucidated.Methods: Flow cytometry was conducted to determine MDSCs level and two main subpopulations of MDSC: granulocyte-like MDSC(G-MDSC)and monocytic MDSC(M-MDSC).Cytokines assessment,RNA sequencing(RNA-Seq)and immune profiling analysis were performed to determine the biological function of MDSC.In vivo and in vitro experiments were performed to elucidate the detail mechanism.Results:Compared with health volunteers,peripheral blood MDSCs were increased in DLBCL patients including both G-MDSC and M-MDSC.This further resulted in host immune suppression.We identified that increased M-MDSC correlate with the clinical status of DLBCL patients,TNF correlated with M-MDSC and poor prognosis.In vivo and in vitro experiments comfirmed TNF could induce M-MDSC expansion,which could be reversed by Daratumumab.Conclusions: Our results showed tumor TNF expression induced M-MDSC expansion and correlated to unfavorable outcome of DLBCL patients.TNF-induced M-MDSC expansion could be overcome by Daratumumab.