Mantle cell lymphoma （MCL） is an aggressive histotype of B-cell non-Hodgkin lymphoma. The disease has no known cure, which prompts the urgent need for novel therapeutic agents. Chromosomal region maintenance 1 （CRM...Mantle cell lymphoma （MCL） is an aggressive histotype of B-cell non-Hodgkin lymphoma. The disease has no known cure, which prompts the urgent need for novel therapeutic agents. Chromosomal region maintenance 1 （CRM1） may play a role in human neoplasia and serve as a novel target of cancer treatment. This study summarizes MCL pathogenesis and determines the involvement of CRM1 in the regulation of several vital signaling pathways contributing to MCL pathogenesis, including the pathways of cell cycle progression, DNA damage response, phosphoinositide kinase-3, nuclear factor-kB activation, and chromosomal stability. A preclinical study is also presented to compare the CRNI1 status in MCL cell lines and primary MCL cells with normal B cells, as well as the therapeutic efficiency of CRM1 inhibition in MCL in vitro and in vivo, which make these agents potential targets of novel MCL treatments.展开更多
Aim:Multiple myeloma(MM)is a hematological malignancy of antibody-producing mature B cells or plasma cells.The proteasome inhibitor,bortezomib,was the first-in-class compound to be FDA approved for MM and is frequentl...Aim:Multiple myeloma(MM)is a hematological malignancy of antibody-producing mature B cells or plasma cells.The proteasome inhibitor,bortezomib,was the first-in-class compound to be FDA approved for MM and is frequently utilized in induction therapy.However,bortezomib refractory disease is a major clinical concern,and the efficacy of the pan-histone deacetylase inhibitor(HDACi),panobinostat,in bortezomib refractory disease indicates that HDAC targeting is a viable strategy.Here,we utilized isogenic bortezomib resistant models to profile HDAC expression and define baseline and HDACi-induced expression patterns of individual HDAC family members in sensitive vs.resistant cells to better understanding the potential for targeting these enzymes.Methods:Gene expression of HDAC family members in two sets of isogenic bortezomib sensitive or resistant myeloma cell lines was examined.These cell lines were subsequently treated with HDAC inhibitors:panobinostat or vorinostat,and HDAC expression was evaluated.CRISPR/Cas9 knockdown and pharmacological inhibition of specific HDAC family members were conducted.Results:Interestingly,HDAC6 and HDAC7 were significantly upregulated and downregulated,respectively,in bortezomib-resistant cells.Panobinostat was effective at inducing cell death in these lines and modulated HDAC expression in cell lines and patient samples.Knockdown of HDAC7 inhibited cell growth while pharmacologically inhibiting HDAC6 augmented cell death by panobinostat.Conclusion:Our data revealed heterogeneous expression of individual HDACs in bortezomib sensitive vs.resistant isogenic cell lines and patient samples treated with panobinostat.Cumulatively our findings highlight distinct roles for HDAC6 and HDAC7 in regulating cell death in the context of bortezomib resistance.展开更多
Multiple myeloma （MM） remains an incurable neoplastic disease, although high-dose chemotherapy supported by autologous stem cells, and the latest integration of several novel agents, including thalidomide, bortezomi...Multiple myeloma （MM） remains an incurable neoplastic disease, although high-dose chemotherapy supported by autologous stem cells, and the latest integration of several novel agents, including thalidomide, bortezomib and lenalidomide, into each step of therapeutics have substantially improved the outcome of patients with MM.1-5 Herein, we gave our own considerations on some promising directions in the near future, aiming at further improving the survival and the quality of life of MM patients, and even achieving our final goal of the cure of MM, including highlighting stratified and individualized therapies, pursuing novel targets and strategies, unraveling the biological characteristics of myeloma initiation cells and strengthening post-transplant immunotherapies.展开更多
Background： The established clinical staging systems （Rai/Binet） of chronic lymphocytic leukemia （CLL） cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decade...Background： The established clinical staging systems （Rai/Binet） of chronic lymphocytic leukemia （CLL） cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together, To predict the time to first treatment （TTFT） in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index （CLL-PI）. Methods： Taking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region （1GI：tV） in CLL-PI. The median follow-up time was 45 months and the end point was TTFT. Results： The median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages （P 〈 0.001） or with 11q- （P = 0.002）, 17p- （P 〈 0.001）, unmutated IGHV （P 〈 0.001）, negative 13q- （P = 0.007） and elevated lactate dehydrogenase levels （P = 0.001 ） tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified： advanced clinical stage （P = 0.002）, 17p- （P = 0.050） and unmutated 1GHV （P = 0.049）. Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize tbur different risk groups （low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3-6]） with significantly different TTFT （median TTFT of not reached （NR）, 65.0 months, 36.0 months and 19.0 months, respectively, P 〈 0.001 ）. Conclusions： This study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.展开更多
基金supported in part by grants from Fujian Provincial Department of Science & Technology(2009-CXB-57/ 2011J01252)Bureau of Science & Technology of Xiamen,China (3502Z20094012)
文摘Mantle cell lymphoma （MCL） is an aggressive histotype of B-cell non-Hodgkin lymphoma. The disease has no known cure, which prompts the urgent need for novel therapeutic agents. Chromosomal region maintenance 1 （CRM1） may play a role in human neoplasia and serve as a novel target of cancer treatment. This study summarizes MCL pathogenesis and determines the involvement of CRM1 in the regulation of several vital signaling pathways contributing to MCL pathogenesis, including the pathways of cell cycle progression, DNA damage response, phosphoinositide kinase-3, nuclear factor-kB activation, and chromosomal stability. A preclinical study is also presented to compare the CRNI1 status in MCL cell lines and primary MCL cells with normal B cells, as well as the therapeutic efficiency of CRM1 inhibition in MCL in vitro and in vivo, which make these agents potential targets of novel MCL treatments.
基金Relevant to this study,Chandra J has received research support from Karus Pharmaceuticals and Novartis PharmaceuticalsOrlowski RZ would like to acknowledge support from the National Cancer Institute(R01s CA184464 and CA194264)the Leukemia&Lymphoma Society Specialized Center of Research(SCOR-12206-17),and Dr.Miriam and Sheldon G.Adelson Research Foundation.
文摘Aim:Multiple myeloma(MM)is a hematological malignancy of antibody-producing mature B cells or plasma cells.The proteasome inhibitor,bortezomib,was the first-in-class compound to be FDA approved for MM and is frequently utilized in induction therapy.However,bortezomib refractory disease is a major clinical concern,and the efficacy of the pan-histone deacetylase inhibitor(HDACi),panobinostat,in bortezomib refractory disease indicates that HDAC targeting is a viable strategy.Here,we utilized isogenic bortezomib resistant models to profile HDAC expression and define baseline and HDACi-induced expression patterns of individual HDAC family members in sensitive vs.resistant cells to better understanding the potential for targeting these enzymes.Methods:Gene expression of HDAC family members in two sets of isogenic bortezomib sensitive or resistant myeloma cell lines was examined.These cell lines were subsequently treated with HDAC inhibitors:panobinostat or vorinostat,and HDAC expression was evaluated.CRISPR/Cas9 knockdown and pharmacological inhibition of specific HDAC family members were conducted.Results:Interestingly,HDAC6 and HDAC7 were significantly upregulated and downregulated,respectively,in bortezomib-resistant cells.Panobinostat was effective at inducing cell death in these lines and modulated HDAC expression in cell lines and patient samples.Knockdown of HDAC7 inhibited cell growth while pharmacologically inhibiting HDAC6 augmented cell death by panobinostat.Conclusion:Our data revealed heterogeneous expression of individual HDACs in bortezomib sensitive vs.resistant isogenic cell lines and patient samples treated with panobinostat.Cumulatively our findings highlight distinct roles for HDAC6 and HDAC7 in regulating cell death in the context of bortezomib resistance.
文摘Multiple myeloma （MM） remains an incurable neoplastic disease, although high-dose chemotherapy supported by autologous stem cells, and the latest integration of several novel agents, including thalidomide, bortezomib and lenalidomide, into each step of therapeutics have substantially improved the outcome of patients with MM.1-5 Herein, we gave our own considerations on some promising directions in the near future, aiming at further improving the survival and the quality of life of MM patients, and even achieving our final goal of the cure of MM, including highlighting stratified and individualized therapies, pursuing novel targets and strategies, unraveling the biological characteristics of myeloma initiation cells and strengthening post-transplant immunotherapies.
基金This work was supported by grants from the National Natural Science Foundation of China （No. 81370632, 81200395）, the National Science and Technology Supporting Program （No. 2014BAI09B 12）, the Fundamental Application and Advanced Technology Research Program of Tianjin （No. 15JCYBJC27900）, and the National Public Health Grand Research Foundation （No. 201202017）.
文摘Background： The established clinical staging systems （Rai/Binet） of chronic lymphocytic leukemia （CLL） cannot accurately predict the appropriate treatment of patients in the earlier stages. In the past two decades, several prognostic factors have been identified to predict the outcome of patients with CLL, but only a few studies investigated more markers together, To predict the time to first treatment （TTFT） in patients of early stages, we evaluated the prognostic role of conventional markers as well as cytogenetic abnormalities and combined them together in a new prognostic scoring system, the CLL prognostic index （CLL-PI）. Methods： Taking advantage of a population of 406 untreated Chinese patients with CLL at early and advanced stage of disease, we identified the strongest prognostic markers of TTFT and, subsequently, in a cohort of 173 patients who had complete data for all 3 variables, we integrated the data of traditional staging system, cytogenetic aberrations, and mutational status of immunoglobulin heavy chain variable region （1GI：tV） in CLL-PI. The median follow-up time was 45 months and the end point was TTFT. Results： The median TTFT was 38 months and the 5-year overall survival was 80%. According to univariate analysis, patients of advanced Rai stages （P 〈 0.001） or with 11q- （P = 0.002）, 17p- （P 〈 0.001）, unmutated IGHV （P 〈 0.001）, negative 13q- （P = 0.007） and elevated lactate dehydrogenase levels （P = 0.001 ） tended to have a significantly shorter TTFT. And subsequently, based on multivariate Cox regression analysis, three independent factors for TTFT were identified： advanced clinical stage （P = 0.002）, 17p- （P = 0.050） and unmutated 1GHV （P = 0.049）. Applying weighted grading of these independent factors, a CLL-PI was constructed based on regression parameters, which could categorize tbur different risk groups （low risk [score 0], intermediate low [score 1], intermediate high [score 2] and high risk [score 3-6]） with significantly different TTFT （median TTFT of not reached （NR）, 65.0 months, 36.0 months and 19.0 months, respectively, P 〈 0.001 ）. Conclusions： This study developed a weighted, integrated CLL-PI prognostic system of CLL patients which combines the critical genetic prognostic markers with traditional clinical stage. This novel modified PI system could be used to discriminate among groups and may help predict the TTFT and prognosis of patients with CLL.
