Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a cru...Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.展开更多
Spurred by better understanding of disease biology,improvements in molecular diagnostics,and the development of targeted therapies,the treatment of acute myeloid leukemia(AML)has undergone significant evolution in rec...Spurred by better understanding of disease biology,improvements in molecular diagnostics,and the development of targeted therapies,the treatment of acute myeloid leukemia(AML)has undergone significant evolution in recent years.Arguably,the most exciting shift has come from the success of treatment with the B-cell lymphoma-2 inhibitor venetoclax.When given in combination with a hypomethylating agent or low dose cytarabine,venetoclax demonstrates high response rates,some of which are durable.In spite of this,relapses after venetoclax treatment are common,and much interest exists in elucidating the mechanisms of resistance to the drug.Alterations in leukemic stem cell metabolism have been identified as a possible escape route,and clinical trials focusing on targeting metabolism in AML are ongoing.This review article highlights current research regarding venetoclax treatment and resistance in AML with a focus on cellular metabolism.展开更多
目的探讨CMYC、BCL_2与BCL_6蛋白表达与弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者临床特征及预后的关系。方法采用免疫组织化学染色法检测我院于2012年1月至2014年4月收集的85例DLBCL患者病理组织标本中CMYC、BCL_...目的探讨CMYC、BCL_2与BCL_6蛋白表达与弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者临床特征及预后的关系。方法采用免疫组织化学染色法检测我院于2012年1月至2014年4月收集的85例DLBCL患者病理组织标本中CMYC、BCL_2、BCL_6、CD10、MUM-1蛋白的表达情况。结果 CMYC、BCL_2、BCL_6蛋白表达阳性率分别为29.4%(25/85)、58.8%(50/85)、69.4%(59/85),其在患者年龄、性别、临床分期、原发部位、血清LDH水平、化疗方案、IPI评分、A/B症状和骨髓侵犯等临床特征之间的表达无显著差异(P>0.05)。单因素生存分析显示,CMYC阴性和BCL_2阴性患者中位OS和中位PFS均显著长于阳性患者(P<0.05),BCL_6阳性和阴性患者中位OS和中位PFS比较差异无统计学意义(P>0.05)。Cox多因素分析显示,CMYC状态可作为DLBCL患者OS和PFS的独立预测指标,差异均具有统计学意义(P<0.05)。结论 CMYC可作为预测DLBCL患者预后的独立有效指标,并可在临床进行应用。展开更多
基金This work was supported by the Major Subject of Science and Technology of Anhui Province(Grant Number:201903a07020030).
文摘Background:The primary cause of treatment failure in patients with refractory or relapsed B-cell non-Hodgkin lymphoma(r/r B-NHL)is resistance to current therapies,and therapy-induced senescence(TIS)stands out as a crucial mechanism contributing to tumor drug resistance.Here,we analyzed SENEX/Rho GTPase Activating Protein 18(ARHGAP18)expression and prognostic significance in doxorubicin-induced B-NHL-TIS model and r/r B-NHL patients,investigating its target in B-NHL cell senescence and the effect of combining specific inhibitors on apoptosis resistance in B-NHL-TIS cells.Methods:Raji cells were transfected with the human SENEX shRNA recombinant lentiviral vector(Sh-SENEX)and the empty vector negative(NC)to construct a stable transfection cell line with knockdown of SENEX.Effect of SENEX-silencing on B-NHL-TIS formation,cell function and cell cycle-related pathways was analyzed.Using doxorubicin(DOX)-inducible senescent B-NHL cells combined with the specific cyclin dependent kinase 4/6(CDK4/6)inhibitor Palbociclib to observe that blocking CDK4/6 effects on TIS formation.SENEX expression of 21 B-NHL patients and 8 healthy controls were analyzed by qRT-PCR,and the correlation between its expression and clinical indicators were evaluated.Results:The downregulation of SENEX expression promotes G1-S phase transition and apoptosis while inhibiting cell proliferation,collectively suppressing the formation of TIS in B-NHL.Blockade of CDK4/6 promotes the DOX-induced G1 phase arrest to enhance TIS formation in B-NHL cells which can reverse the regulatory effect of silencing SENEX on B-NHL cell cycle regulation and senescence.The expression levels of SENEX were notably elevated in B-NHL patients compared to healthy controls,and Elevated expression levels of SENEX were associated with poor prognosis of B-NHL patients.Conclusions:SENEX enhances apoptosis resistance in B-NHL by inhibiting CDK4/6,thereby preventing G1-S phase transition and promoting TIS formation.
文摘Spurred by better understanding of disease biology,improvements in molecular diagnostics,and the development of targeted therapies,the treatment of acute myeloid leukemia(AML)has undergone significant evolution in recent years.Arguably,the most exciting shift has come from the success of treatment with the B-cell lymphoma-2 inhibitor venetoclax.When given in combination with a hypomethylating agent or low dose cytarabine,venetoclax demonstrates high response rates,some of which are durable.In spite of this,relapses after venetoclax treatment are common,and much interest exists in elucidating the mechanisms of resistance to the drug.Alterations in leukemic stem cell metabolism have been identified as a possible escape route,and clinical trials focusing on targeting metabolism in AML are ongoing.This review article highlights current research regarding venetoclax treatment and resistance in AML with a focus on cellular metabolism.
文摘目的探讨CMYC、BCL_2与BCL_6蛋白表达与弥漫性大B细胞淋巴瘤(diffuse large B cell lymphoma,DLBCL)患者临床特征及预后的关系。方法采用免疫组织化学染色法检测我院于2012年1月至2014年4月收集的85例DLBCL患者病理组织标本中CMYC、BCL_2、BCL_6、CD10、MUM-1蛋白的表达情况。结果 CMYC、BCL_2、BCL_6蛋白表达阳性率分别为29.4%(25/85)、58.8%(50/85)、69.4%(59/85),其在患者年龄、性别、临床分期、原发部位、血清LDH水平、化疗方案、IPI评分、A/B症状和骨髓侵犯等临床特征之间的表达无显著差异(P>0.05)。单因素生存分析显示,CMYC阴性和BCL_2阴性患者中位OS和中位PFS均显著长于阳性患者(P<0.05),BCL_6阳性和阴性患者中位OS和中位PFS比较差异无统计学意义(P>0.05)。Cox多因素分析显示,CMYC状态可作为DLBCL患者OS和PFS的独立预测指标,差异均具有统计学意义(P<0.05)。结论 CMYC可作为预测DLBCL患者预后的独立有效指标,并可在临床进行应用。
