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Exploiting the potential of the ubiquitin-proteasome system in overcoming tyrosine kinase inhibitor resistance in chronic myeloid leukemia

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Genes & Diseases 2024年第5期11卷 140-162页

作者： Xudong Li Wei Li Yanli Zhang Linping Xu yongping song Department of Hematology Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhouHenan 450008China Academy of Medical Sciences Zhengzhou UniversityZhengzhouHenan 450052China Department of Hematology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China

The advent of tyrosine kinase inhibitors(TKI)targeting BCR-ABL has drastically changed the treatment approach of chronic myeloid leukemia(CML),greatly prolonged the life of CML patients,and improved their ***,TKI resistance is still a major problem with CML patients,reducing the efficacy of treatment and their quality of *** resistance is mainly divided into BCR-ABL-dependent and BCR-ABL-independent ***,the main clinical strategy addressing TKI resistance is to switch to newly developed ***,data have shown that these new drugs may cause serious adverse reactions and intolerance and cannot address all resistance ***,finding new therapeutic targets to overcome TKI resistance is crucial and the ubiquitin-proteasome system(UPS)has emerged as a *** UPS mediates the degradation of most proteins in organisms and controls a wide range of physiological *** recent years,the study of UPS in hematological malignant tumors has resulted in effective treatments,such as bortezomib in the treatment of multiple myeloma and mantle cell *** CML,the components of UPS cooperate or antagonize the efficacy of TKI by directly or indirectly affecting the ubiquitination of BCR-ABL,interfering with CML-related signaling pathways,and negatively or positively affecting leukemia stem *** of these molecules may help overcome TKI resistance and treat *** this review,the mechanism of TKI resistance is briefly described,the components of UPS are introduced,existing studies on UPS participating in TKI resistance are listed,and UPS as the therapeutic target and strategies are discussed.

关键词： Chronic myeloid leukemia Deubiquitinases E3 ligase PROTAC TKI resistance Ubiquitin-proteasome system

Venetoclax and low-dose cytarabine induced complete remissionin a patient with high-risk acute myeloid leukemia： a case report

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Frontiers of Medicine 2018年第5期12卷 593-599页

作者： Bingshan Liu Roshni Narurkar Madhura Hanmantgad Wahib Zafar yongping song Delong Liu The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital Zhengzhou 450003 China Department of Medicine New York Medical College and Westchester Medical Center Valhalla NY 10595 USA

Conventional combination therapies have not resulted in considerable progress in the treatment of acute myeloid leukemia (AML). Elderly patients with AML and poor risk factors have grave prognosis. Midostaurin has been recently approved for the treatment of FLT-3-mutated AML. Venetoclax, a BCL-2 inhibitor, has been approved for the treatment of relapsed and/or refractory chronic lymphoid leukemia. Clinical trials on applying venetoclax in combination with cytarabine and other agents to treat various hematological malignancies are currently underway. Here, we present a case of a male patient with poor performance status and who developed AML following allogeneic hematopoietic stem cell transplant for high-risk myelodysplasia. The patient with high risk AML achieved complete response to the combined treatment regimen of low-dose cytarabine and venetoclax. Furthermore, we reviewed current clinical trials on the use of venetoclax for hematological malignancies.

关键词： AML cytarabine leukemia venetoclax

Pluripotent stem cells exhibiting similar characteristics can be isolated from human fetal bone marrow, heart, liver, muscle, lung, derma, kidney, and fat

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Frontiers of Medicine 2007年第2期1卷 185-191页

作者： FANG Baijun song yongping ZHAO Chunhua SHI Mingxia LIN Quande Henan Tumor Hospital Henan Institute of HematologyZhengzhou 450008China Institute of Basic Medical Sciences Center for Tissue EngineeringChinese Academy of Medical ScienceBeijing 100005China

Previously,we reported that a cell population derived from human fetal bone marrow(BM),termed here Flk1+CD34−postembryonic pluripotent stem cells(PPSCs)that have the characteristics of mesenchymal stem cells(MSCs),could differentiate into ectodermal,endodermal and mesodermal cell types at the single cell level in vitro,and that these cells could also differentiate into the epithelium of liver,lung,gut,as well as the hematopoietic and endothelial lineages after transplantion into irradiated non-obese diabetic/severe combined immunodeficient(NOD/SCID)*** this study,we further isolated pluripotent stem cells from human fetal heart,liver,muscle,lung,derma,kidney,and fat and then analyzed the characteristics and function of these stem *** was found that the phenotype of the culture-expanded pluripotent stem cells from different fetal tissues was similar to BM-derived Flk1^(+)CD34^(−)PPSCs,***1 and CD44 positive,GlyA,CD34,CD45,class I-HLA and HLA-DR ***,these cells were fibroblast-like and the doubling time was about 30 *** importantly,culture-expanded pluripotent stem cells from all these fetal tissues were able to differentiate into cells with morphologic and phenotypic characteristics of adipocytes,osteocytes,neurons,glial cells and *** pluripotent stem cells with characteristics similar to fetal BM-derived Flk1^(+)CD34^(−)PPSCs can be selected and cultured from tissues other than the *** phenomenon may help explain the“stem cell plasticity”found in multiple human *** addition,as fetal BM-derived Flk1^(+)CD34^(−)PPSCs,these pluripotent stem cells from different fetal tissues had the capacity for self-renewal and multi-lineage differentiation even after being expanded for more than 40 population doublings in ***,they may be an ideal source of stem cells for treatment of inherited or degenerative diseases.

关键词： pluripotent stem cells fetal plasticity

Sintilimab for relapsed/refractory extranodal NK/T cell lymphoma: a multicenter, single-arm, phase 2 trial (ORIENT-4)

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Signal Transduction and Targeted Therapy 2021年第11期6卷 3341-3347页

作者： Rong Tao Lei Fan yongping song Yu Hu Wei Zhang Yafei Wang Wei Xu Jianyong Li Department of Hematology Xinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina The First Affiliated Hospital of Nanjing Medical University Jiangsu Province HospitalCollaborative Innovation Center for Cancer Personalized MedicineNanjingChina The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital ZhengzhouChina Union Hospital Tongji Medical College Huazhong University of Science and Technology WuhanChina Peking Union Medical College Hospital BeijingChina Tianjin Medical University Cancer Institute and Hospital TianjinChina

This study(ORIENT-4)aimed to assess the efficacy and safety of sintilimab,a humanized anti-PD-1 antibody,in patients with relapsed/refractory extranodal NK/T cell lymphoma(r/r ENKTL).ORIENT-4 is a multicenter,single-arm,phase 2 clinical trial(NCT03228836).Patients with r/r ENKTL who failed to at least one asparaginase-based regimen were enrolled to receive sintilimab 200 mg intravenously every 3 weeks for up to 24 *** primary endpoint was the objective response rate(ORR)based on Lugano 2014 ***-eight patients with r/r ENKTL were enrolled from August 31,2017 to February 7,***-one patients(75.0%,95%CI:55.1–89.3%)achieved an objective *** a median follow-up of 30.4 months,the median overall survival(OS)was not *** 24-month OS rate was 78.6%(95%CI,58.4–89.8%).Most treatment-related adverse events(TRAEs)were grade 1–2(71.4%),and the most common TRAE was decreased lymphocyte count(42.9%).Serious adverse events(SAEs)occurred in 7(25.0%)patients,and no patient died of adverse *** is effective and well tolerated in patients with r/r ENKTL and could be a novel therapeutic approach for the control of ENKTL in patients.

关键词： lymphoma relapse nodal

Ferroptosis in acute leukemia

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Chinese Medical Journal 2023年第8期136卷 886-898页

作者： Tianxin Lyu Xudong Li yongping song Department of Hematology The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhouHenan 450008China Academy of Medical Sciences Zhengzhou UniversityZhengzhouHenan 450052China Department of Hematology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China

Ferroptosis is an iron-dependent cell death pathway that is different from apoptosis,pyroptosis,and *** main characteristics of ferroptosis are the Fenton reaction mediated by intracellular free divalent iron ions,lipid peroxidation of cell membrane lipids,and inhibition of the anti-lipid peroxidation activity of intracellular glutathione peroxidase 4(GPX4).Recent studies have shown that ferroptosis can be involved in the pathological processes of many disorders,such as ischemia-reperfusion injury,nervous system diseases,and blood ***,the specific mechanisms by which ferroptosis participates in the occurrence and development of acute leukemia still need to be more fully and deeply *** article reviews the characteristics of ferroptosis and the regulatory mechanisms promoting or inhibiting *** importantly,it further discusses the role of ferroptosis in acute leukemia and predicts a change in treatment strategy brought about by increased knowledge of the role of ferroptosis in acute leukemia.

关键词： Acute lymphoblastic leukemia Acute myeloid leukemia Ferroptosis Oxidative damage Antioxidant defense Lipid peroxidation

A Novel Dominant Allele from 93-11, ES(4), Represses Reactive Oxygen Species Scavenging and Leads to Early-Senescence in Rice

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Phyton-International Journal of Experimental Botany 2023年第3期92卷 665-677页

作者： Zhishu Jiang Cong Gan Yulian Liu Xiaoli Lin Limei Peng yongping song Xiaowei Luo Jie Xu Key Laboratory of Crop Physiology Ecology and Genetic BreedingMinistry of EducationJiangxi Agricultural UniversityNanchang330045China

Senescence is the last developmental process in plant,which has an important impact on crop yield and *** this study,a stable hereditary early-senescence line BC64 was isolated from the high-generation recombinant inbred lines of 93-11 and Wuyunjing7(W7).Genetic analysis showed that the premature aging phenotype was controlled by a dominant gene derived from *** linkage analysis,the gene was primarily mapped in the region between marker B4 and B5 near the centromere of chromosome 4,described as ES(4).Through multiple backcrossing with W7,the near-isogenic line of ES(4)(NIL-ES(4))was *** with wild-type W7,NIL-ES(4)plants showed more sever senescence phenotype in both nature and dark *** NIL plants,leaves turned yellow at the fully tillering stage;photosynthetic rate,pollen fertility and seed setting rate were ***,the malondialdehyde,proline content and relative conductivity in NIL-ES(4)were significantly higher than those in W7;both transcript level and activities of reactive oxygen species scavenging enzymes were repressed;H2O2 and O^(2−)were significantly *** study provides a basis for further cloning and function identification of ES(4).

关键词： Rice early-senescence gene mapping chlorophyll degradation reactive oxygen species scavenging

Chimeric antigen receptor-immune cells against solid tumors:Structures,mechanisms,recent advances,and future developments

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Chinese Medical Journal 2024年第11期137卷 1285-1302页

作者： Xudong Li Wei Li Linping Xu yongping song Department of Hematology The Affiliated Cancer Hospital of Zhengzhou University&Henan Cancer HospitalZhengzhouHenan 450008China Department of Hematology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Academy of Medical Sciences Zhengzhou UniversityZhengzhouHenan 450052China

The advent of chimeric antigen receptor(CAR)-T cell immunotherapies has led to breakthroughs in the treatment of hematological ***,their success in treating solid tumors has been ***-natural killer(NK)cells have several advantages over CAR-T cells because NK cells can be made from pre-existing cell lines or allogeneic NK cells with a mismatched major histocompatibility complex(MHC),which means they are more likely to become an"off-the-shelf"***,they can kill cancer cells via CAR-dependent/independent pathways and have limited *** are the most malleable immune cells in the *** cells can efficiently infiltrate into tumors and are present in large numbers in tumor microenvironments(TMEs).Importantly,CAR-macrophages(CAR-Ms)have recently yielded exciting preclinical results in several solid ***,CAR-T,CAR-NK,and CAR-M all have their own advantages and *** this review,we systematically discuss the current status,progress,and the major hurdles of CAR-T cells,CAR-NK cells,and CAR-M as they relate to five aspects:CAR structure,therapeutic mechanisms,the latest research progress,current challenges and solutions,and comparison according to the existing research in order to provide a reasonable option for treating solid tumors in the future.

关键词： Immunotherapy Chimeric antigen receptor-T cells Chimeric antigen receptor-NK cells Chimeric antigen receptor-macrophage Solid tumors

Immune cells in the B-cell lymphoma microenvironment:From basic research to clinical applications

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Chinese Medical Journal 2024年第7期137卷 776-790页

作者： Wenli Zhang Mengmeng Liu Wei Li yongping song Department of Hematology The First Affiliated Hospital of Zhengzhou UniversityZhengzhouHenan 450052China Department of Hematology Henan Provincial Hematology HospitalZhengzhouHenan 450000China Academy of Medical Sciences Zhengzhou UniversityZhengzhouHenan 450052China Department of Research and Foreign Affairs The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhouHenan 450008China

B-cell lymphoma is a group of hematological malignancies characterized by variable genetic and biological features and clinical *** tumor microenvironment(TME)is a complex network in tumors,which consists of surrounding blood vessels,extracellular matrix,immune and non-immune cells,and signaling *** evidence has shown that the TME,especially immune cells within,is a double-edged sword,acting either as a tumor killer or as a promoter of tumor *** pro-tumor activities are driven by subpopulations of immune cells that express typical markers but have unique transcriptional characteristics,making tumor-associated immune cells good targets for human anti-cancer therapy by ablating immunosuppressive cells or enhancing immune-activated ***,exploring the role of immune cells in the TME provides distinct insights for immunotherapy in B-cell *** this review,we elucidated the interaction between immune cells and tumor cells and their function in the initiation,progression,and prognosis of B-cell lymphoma,from preclinical experiments to clinical ***,we outlined potential therapeutic approaches and discussed the potential clinical value and future perspectives of targeting immune cells in patients with B-cell lymphoma.

关键词： Tumor microenvironment B-cell lymphoma Immune cells Immunotherapy Targeted therapy

Culturing adequate CAR-T cells from less peripheral blood to treat B-cell malignancies

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Cancer Biology & Medicine 2021年第4期18卷 1066-1079页

作者： Lu Han Jian Zhou Linlin Li Keshu Zhou Lingdi Zhao Xinghu Zhu Qingsong Yin Yufu Li Hongqin You Jishuai Zhang yongping song Quanli Gao Department of Immunology Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhou 450008China Department of Hematology Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer HospitalZhengzhou 450008China Department of Medical Microbiology School of Basic Medical SciencesXinxiang Medical UniversityXinxiang 453003China The Shenzhen Pregene Biopharma Company Ltd.Shenzhen 518118China

Objective:Chimeric antigen receptor-modified T(CAR-T)cells have shown impressive results against relapsed/refractory B cell ***,the traditional manufacture of CAR-T cells requires leukapheresis to isolate large amounts of peripheral blood T cells,thus making some patients ineligible for the ***:We developed a simple method for CAR-T cell preparation requiring small volumes of peripheral ***,CD3+T cells isolated from 50 mL peripheral blood from patients(B-cell malignancies)were stimulated with immobilized anti-CD3/RetroNectin in 6-well plates and then transduced with CAR-expressing lentiviral *** 4 d,the T cells were transferred to culture bags for large-scale CAR-T cell *** vitro and animal experiments were performed to evaluate the activity of the manufactured CAR-T ***,29 patients with B-cell acute lymphoblastic leukemia(B-ALL)and 9 patients with B-cell lymphoma were treated with the CAR-T ***:The CAR-T cells were expanded to 1–3×10^(8) cells in 8–10 d and successfully killed B cell-derived malignant tumor cells in vitro and in *** patients with B-ALL,the complete remission rate was 93%1 month after CAR-T cell infusion;after 12 months,the overall survival(OS)and leukemia-free survival rates were 69%and 31%,*** patients with lymphoma,the objective response rate(including complete and partial remission)was 78%2 months after CAR-T cell infusion,and after 12 months,the OS and progression-free survival rates were 71%and 43%,***-release syndrome(CRS)occurred in 65.51%and 55.56%of patients with B-ALL and B-cell lymphoma,respectively;severe CRS developed in 20.69%of patients with B-ALL and in no patients with ***:Our novel method can generate sufficient numbers of CAR-T cells for clinical use from 50–100 mL peripheral blood,thus providing an alternative means of CAR-T cell generation for patients ineligible for leukapheresis.

关键词： Fewer initial lymphocytes peripheral blood CAR-T cells B-cell malignancy acute lymphoblastic leukemia