Studies On The Mechanism Of Deacetylase Inhibitors In Hematological Malignancies

T-cell lymphoma is a heterogeneous non Hodgkin's lymphoma with abnormal proliferation of T-lymphocytes,patients often resistant to chemotherapy and easy to relapse.Currently,there is no effective therapy for T-cell lymphoma.In recent years,histone deacetylase inhibitors have attracted more and more attention due to their strong anti-tumor effect.In our study,We found that histone deacetylase inhibitor Vorinostat(SAHA),which has been approved by U.S.Food and Drug Administration(FDA)for the treatment of cutaneous T-cell lymphoma,can promote the death of T-cell lymphoma cells.However,SAHA also induced autophagy,which limited it?s anti-tumor effect.Future more,we found that an anti-malarial quinacrine(QC)had a considerable synergistic effect with SAHA in promoting T-cell lymphoma cells death.QC in combination with SAHA induced an increase of intracellular reactive oxygen species(ROS),further increased mitochondrial dysfunction and the accumulation of mitochondrial K63-ubiquitinated proteins which indicated mitophagy.However,QC blocked autophagy flow through causing lysosomal dysfunction,and then leaded to an accumulation of mitochondria aggresomes,eventually inducing T-cell lymphoma cells death.This research has an important practical significance in providing a new therapeutic regimen for the treatment of T-cell lymphoma.Retinoic acid was successfully used for the treatment of acute promyelocytic leukemia by inducing differentiation.However,retinoic acid induces cell differentiation accompanied with the degradation of transcription factor RAR? protein,weaking differentiation induced.In our study,we screened a histone deacetylase inhibitor valproic acid can stabilize RAR? protein in cells by establishing a double fluorescence NB4 cell screening model,which provided a new mechanism for the differentiation induced by valproic acid.