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From dissection of disease pathogenesis to elucidation of mechanisms of targeted therapies:leukemia research in the genomic era

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Acta Pharmacologica Sinica 2007年第9期28卷 1434-1449页

作者： guang-blao zhou~(1,2),guo li~1,sai-juan chen~1,zhu chen~(1,3)~1 state key laboratory of medical genomics and shanghai institute of hematology,rui jin hospital affiliated to shanghai jiao tonguniversity school of medicine,shanghai 200025, china ~2 guangzhou institute of Biomedicine and Health,Chinese Academy of Sciences,guangzhou 510663,china state key laboratory of medical genomics and shanghai institute of hematology Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China guangzhou institute of Biomedicine and Health Chinese Academy of Sciences Guangzhou China

Leukemia is a group of heterozygous diseases of hematopoietic stem/progenitorcells that involves dynamic change in the *** of genetic abnor-malities critical to leukemia initiation provides insights into the elusiveleukemogenesis,identifies distinct subsets of leukemia and predicts prognosisindividually,and can also provide rational therapeutic targets for *** past three decades have seen tremendous advances in theanalysis of genotype-phenotype connection of leukemia,and in the identifica-tion of molecular biomarkers for leukemia ***,differentiationtherapy,targeted therapy and chemotherapy have turned several subtypes ofleukemia from highly fatal to highly *** use of all-trans retinoic acid andarsenic trioxide,which trigger degradation of PML-RARα,the causative fusionprotein generated by t (15;17) translocation in acute promyelocytic leukemia (APL),has led to a dramatic improvement of APL clinical outcome,lmatinib mesylate/Gleevec/STI571,which inhibits the tyrosine kinase activity of BCR-ABLoncoprotein,has now become the new gold standard for the treatmtent of chronicmyeloid *** use of chemotherapeutic agents together with a strin-gent application of prognostic factors for risk-directed therapy in clinical trialshas resulted in a steady improvement in the treatment outcome of acute lympho-blastic ***,the pace of progress extrapolates to a prediction ofleukemia control in the twenty-first century.

关键词： leukemia genomics cancer therapy

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Antigen-induced chimeric antigen receptor multimerization amplifies on-tumor cytotoxicity

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Signal Transduction and Targeted Therapy 2024年第1期9卷 259-270页

作者： Yan Sun Xiu-Na Yang Shuang-Shuang Yang Yi-zhu Lyu Bing Zhang Kai-Wen liu Na li Jia-chen Cui guang-Xiang Huang cheng-lin liu Jie Xu Jian-Qing Mi zhu chen Xiao-Hu Fan sai-juan chen Shuo chen shanghai institute of hematology National Research Center for Translational MedicineState Key Laboratory of Medical GenomicsRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China shanghai institute for Advanced Immunochemical Studies and school of life Science and Technology ShanghaiTech UniversityShanghai 201210China Department of hematology Second Hospital of Dalian Medical UniversityDalian 116023China National Facility for Protein Science shanghai Shanghai Advanced Research InstituteChinese Academy of SciencesShanghai 201210China Legend Biotech china Nanjing 211112China shanghai Immune Therapy institute Shanghai Cancer InstituteState Key Laboratory of Oncogenes and Related GenesRenji Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200127China Wondercel Biotechnology Shenzhen 518052China

ligand-induced receptor dimerization or oligomerization is a widespread mechanism for ensuring communication specificity,safeguarding receptor activation,and facilitating amplification of signal transduction across the cellular ***,cell-surface antigeninduced multimerization(dubbed AIM herein)has not yet been consciously leveraged in chimeric antigen receptor(CAR)engineering for enriching T cell-based *** co-developed ciltacabtagene autoleucel(cilta-cel),whose CAR incorporates two B-cell maturation antigen(BCMA)-targeted nanobodies in tandem,for treating multiple *** we elucidated a structural and functional model in which BCMA-induced cilta-cel CAR multimerization amplifies myeloma-targeted T cell-mediated *** analysis of BCMA–nanobody complexes revealed atomic details of antigen–antibody hetero-multimerization whilst analytical ultracentrifugation and small-angle X-ray scattering characterized interdependent BCMA apposition and CAR juxtaposition in ***-induced nanobody CAR multimerization enhanced cytotoxicity,alongside elevated immune synapse formation and cytotoxicity-mediating cytokine release,towards myeloma-derived *** results provide a framework for contemplating the AIM approach in designing next-generation CARs.

关键词： cytotoxicity Antigen elevated

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Back to the future of oridonin: again,compound from medicinal herb shows potent antileukemia efficacies in vitro and in vivo

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Cell Research 2007年第4期17卷 274-276页

作者： guang-Biao zhou~(1,2) sai-juan chen~1 Zhen-Yi Wang~1 zhu chen~1 ~1state key laboratory of medical genomics and shanghai institute of hematology,ruijin hospital affiliated to shanghai jiao Tong University school of medicine,197 ruijin Road II,shanghai 200025,china ~2guangzhou institute of Biomedicine and Health,Chinese Academy of Sciences,guangzhou Science Park,guangzhou 510663,china state key laboratory of medical genomics and shanghai institute of hematology Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine Shanghai China guangzhou institute of Biomedicine and Health Chinese Academy of Sciences Guangzhou Science Park Guangzhou China

Traditional Chinese medicine(TCM)has been widelyand successfully used in treating illnesses ranging frominflammation to cancer,and compounds from medicinalherbs and minerals are playing more and more importantroles in taming various kinds of diseases[1],exemplifiedby artemisinin and arsenic trioxide(ATO).Artemisinin(or Qinghaosu in Chinese)is isolated from a plant calledsweet wormwood(Artemisia annua;or Qinghao in Chi-nese)which has been used as an antipyretic remedy formore than 1500 years in *** has impressiveparasiticidal properties in vitro and in vivo,and is now oneof the most important class of antimalarial agents[2,3].ATO is a common,naturally occurring substance whichhad been used in china for a long time as a therapeuticagent for some severe diseases with the ancient philosophyof'treating an evil with a toxic'[4].In 1990s,ATO wasshown to be able to cause partial differentiation at low doseand apoptosis at high concentration of acute promyelocyticleukemia(APL)cells[5],and induce complete remissionin 90% of patients with relapsed or refractory APL[6-8].

关键词： AML Back to the future of oridonin again,compound from medicinal herb shows potent antileukemia efficacies in vitro and in vivo

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Disruption of palladin leads to defects in definitive erythropoiesis by interfering erythroblastic island formation in mouse fetal liver

Disruption of palladin leads to defects in definitive erythr...

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中国遗传学会“发育、遗传和疾病”研讨会

作者： Xue-Song liu~(1,4) Xi-Hua li~1 Yi Wang~1 Run-Zhe Shu~(1,4) Long Wang~(1-3) Shun-Yuan Lu~(1-3) Hui Kong~3 Yue-E jin~1 li-Jun Zhang~1 Jian Fei~3 sai-juan chen~2 zhu chen~2 Ming-Min Gu~1 Zhen-Yu Lu~1 zhu-Gang Wang~(1-3,*) 1 laboratory of Genetic Engineering,institute of Health Sciences,shanghai institutes for Biological Sciences,Chinese Academy of Sciences & shanghai jiao Tong University school of medicine,shanghai 200025,PR china 2 state key laboratory of medical genomics,rui-jin hospital affiliated to shanghai jiao Tong University school of medicine,shanghai 200025,PR china 3 shanghai Research Center for Model Organisms,shanghai 201203,PR china 4 Graduate school of Chinese Academy of Sciences,shanghai 200025,PR china.

Palladin was originally found up-regulated with NB4 cell differentiation induced by *** of palladin results in neural tube closure defects,liver herniation and embryonic *** we further report thatpailadinembryos exhibit a significant defect in erythropoiesis,characterized by dramatic reduction in definitive erythrocytes derived from fetal liver but not primitive erythrocytes from yolk *** reduction of erythrocytes is accompanied by increased apoptosis of erythroblasts and partial blockage of erythroid ***,colony forming assay shows no differences between wt and mutant fetal liver or yolk sac in the number and size of colonies *** addition,palladinfetal liver cells can reconstitute hematopoiesis in lethally-irradiated *** data strongly suggest that deficient erythropoiesis in palladin fetal liver is mainly due to compromised erythropoietic *** expected,erythroblastic island in palladin fetal liver was found *** liver cells fail to form erythroblastic island in ***,wt macrophages can form such units with either wt or mutant erythroblasts,while mutant macrophages lose their ability to bind wt or mutant *** data demonstrate that palladin is crucial for definitive erythropoiesis and erythroblastic island formation,and especially,required for normal function ofmacrophages in fetal liver.

关键词： Palladin Fetal liver Erythropoiesis Microenvironment Macrophage.

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Enhanced Antileukemia Efficacy but not Cardiotoxicity Exerted by Proteasome Inhibitor/Imatinib Combinations in Chronic Myeloid Leukemia

Enhanced Antileukemia Efficacy but not Cardiotoxicity Exerte...

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第五届全国化学生物学学术会议

作者： Zheng Hu~1 Xiao-Fen Pan~1 jing-Lei liu~(1,5) Da-Peng liu~1 Xiao-li liu~2 Fan-Yi Meng~2 Feng-Xiang Zhang~1 Fu-Qun Wu~1 juan li~4 zhu chen~3 sai-juan chen~3 guang-Biao zhou~(1*) 1 laboratory of Molecular Target-Based Therapy for Cancer,guangzhou institute of Biomedicine and Health,Chinese Academy of Sciences,guangzhou 510663 2 Department of hematology,Nanfang hospital affiliated to Nanfang medical University,guangzhou,510515 3 state key laboratory of medical genomics and shanghai institute of hematology, rui jin hospital affiliated to shanghai jiao Tong University school of medicine,shanghai, 200025 4 Department of hematology,the First affiliated hospital,Sun Yat-Sen University,guangzhou,510080 5 University of Science and Technology of china,Hefei,230027,china.

＜正＞Resistance developed by leukemic cells,cardiotoxity,and unsatisfactory efficacy on patients with chronic myeloid leukemia（CML）at accelerated and blastic phases,have been limitations for imatinib mesylate（IM）in treating *** IM based combinatory regimens could be one of the strategies to overcome these limitations needs more *** we showed that the

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A Transgenic Zebrafish Model of Macrophage Migration and Chemotaxis

A Transgenic Zebrafish Model of Macrophage Migration and Che...

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中国遗传学会“发育、遗传和疾病”研讨会

作者： Yong Zhang~1 Xue-Tao Bai~1 Yi jin~(1,2) Min Deng~2 Yi chen~(1,2) Huang-Ying Le~(1,2) Yah-Fang Fu~2 Xiao-Jian Sun~(1,2) Jiang zhu~1 zhu chen~(1,4) sai-juan chen~1 Ting Xi liu~(1,2,3) 1.state key laboratory for medical genomics and shanghai institute of hematology,ruijin hospital affiliated to shanghai jiao Tong University school of medicine,shanghai 200025,china 2.laboratory of Development and Diseases,institute of Health Sciences,shanghai institutes for Biological Sciences,Chinese Academy of Sciences & shanghai jiao Tong University school of medicine,shanghai 20002,china 3.Model Organism Division,E-institutes of shanghai Universities,shanghai 200025,china 4.shanghai Center for Systems Biomedicine,shanghai jiao Tong University,shanghai 200240,china

We have established an in vivo model for visualizing the developmental and chemotactic movement of primitive macrophages,by generating a stable transgenic line expressing EGFP under the zebrafish lysozyme C promoter [TG(zlyz:EGFP)].We show that the earliest macrophages originate from the head mesenchyme nearby the bilateral plate mesoderm at～22 hpf,then migrate either within the head or toward the yolk sac close to the circulation *** macrophages subsequently colonize the posterior intermediate cell mass(ICM)through ***,the resident macrophages,but not the circulating macrophages,migrate rapidly to the site of inflammation induced by tail transection,with their number peaking at approximately 5-6 hours after *** hours post-injury,these recruited macrophages initiate retrograde migration from the inflamed tail back to the ICM mesenchyme,suggesting a resolution of the ***,an anti-inflammatory glucocorticoid hormone (dexamethasone)suppresses both the chemotactic and retrograde migration of macrophages during the onset and resolution of ***,the TG(zlyz:EGFP)zebrafish provides an invaluable tool not only for elucidating the pleiotropic roles of macrophages in innate immunity,tumorigenesis and organogenesis during embryogenesis,but for identifying the therapeutic small molecules against human disorders associated with deregulated migration and chemotaxis of macrophage in vivo.

关键词： A Transgenic Zebrafish Model of Macrophage Migration and Chemotaxis Model

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Disruption of Rig-I in Mice Triggers Colitis Partially through Down-regulation of Gai2

Disruption of Rig-I in Mice Triggers Colitis Partially throu...

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中国遗传学会“发育、遗传和疾病”研讨会

作者： Yi Wang~1 Hong-Xin Zhang~1 Zi-Xing liu~1 Yue-Ping Sun~1 Xue-Song liu~1 Long Wang~2 Shun-Yuan Lu~2 Hui Kong~3 Qiao-ling liu~3 Xi-Hua li~1 Zhen-Yu Lu~1 sai-juan chen~2 zhu chen~2 Shi-San Bao~4 Wei Dai~5 zhu-Gang Wang~(1-4*) 1.Department of medical Genetics,shanghai jiao Tong University school of medicine,shanghai 200025,china 2.state key laboratory of medical genomics,rui-jin hospital affiliated to shanghai jiao Tong University school of medicine,shanghai 200025,china 3.shanghai Research Center for Model Organisms,shanghai 201203,china 4.Department of Pathology,University of Sydney,Sydney,2570 NSW,Australia 5.Department of Environmental medicine,New York University school of medicine,Tuxedo,NY 10987,USA

RIG-I（Retinoid acid-inducible gene-I）,a putative RNA helicase with cytoplasmic caspase-recruiting domain（CARD）,is identified as a pattern recognition receptor（PRR）mediating antiviral immunity by inducing type I interferon *** further study the biological function of RIG-I,we generated Rig-Imice through homologous recombination by taking different strategy from previously ***-Imice are viable and *** analysis shows that Rig-Imice develop a colitis-like phenotype spontaneously and also increased susceptibility to DSS-induced colitis. Accordingly,the size and number of Peyer's patches dramatically decreased in mutant *** peripheral T cell subsets in mutant mice were characterized by an increase in effector T cells and decreased na（?）ve T cells,indicating an important role of Rig-I in the regulation of T cell *** was further found that Rig-I deficiency leads to down-regulation of Gai2 expression in various tissues including T and B *** contraries,up-regulation of Rig-I in NB4 cells treated with ATRA is accompanied by elevated Gai2 ***,Gai2 promoter activity is increased in co-transfected NIH3T3 cells in a Rig-I dose-related *** these findings suggest that Rig-I plays the crucial roles in the regulation of Gai2 expression and T cell *** development of colitis may be,at least in part,associated with down-regulation of Gai2 and disturbed T cell homeostasis.

关键词： Knockout Mice Gene Regulation Inflammation

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Efficacies of Oridonin on t（8;21） Leukemia

Efficacies of Oridonin on t（8;21） Leukemia

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第五届全国化学生物学学术会议

作者： guang-Biao zhou~(1,2*) Hui Kang~* Lan Wang~(1,3*) li Gao~(1*) Ping liu~1 Jun Xie~2 Feng-Xiang Zhang~2 Xiang-Qin Weng~1 Zhi-Xiang Shen~1 Jue-chen~1 Long-Jun Gu~4 Ming Yan~5 Dong-Er Zhang~5 sai-juan chen~(1,3) Zhen-Yi Wang~1 zhu chen~(1,3) 1 state key laboratory of medical genomics and shanghai institute of hematology,rui jin hospital affiliated to shanghai jiao Tong University school of medicine (SJTUSM),197 rui jin Road Ⅱ,shanghai,200025,P.R.china 2 guangzhou institute of Biomedicine and Health,Chinese Academy of Sciences,guangzhou Science Park,510663 3 shanghai Center for Systems Biomedicine,shanghai jiao Tong University,shanghai, china 4 Children''medical Center,SJTUSM 5 Department of Molecular and Experimental medicine,The Scripps Research institute,La Jolla,CA 92037,USA.

＜正＞Studies have documented the potential antitumor activities of oridonin,a compound extracted from medicinal ***,whether oridonin can be used in selected setting of hematology/oncology remains *** we reported that...

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The liFR-targeting small molecules EC330/EC359 are potent ferroptosis inducers

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Genes & Diseases 2023年第3期10卷 735-738页

作者： Chang-zhou Feng Ning-Zhe li Xi-Bo Hu Yin-Yin Xie Qiu-Hua Huang Jianming Zhang zhu chen sai-juan chen Fudi Wang Xiao-Jian Sun shanghai institute of hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai 200025China school of life Sciences&Biotechnology Shanghai Jiao Tong UniversityShanghai 200240China The First affiliated hospital School of Public HealthInstitute of Translational MedicineZhejiang University School of MedicineHangzhouZhejiang 310058China The First affiliated hospital Hengyang Medical SchoolUniversity of South ChinaHengyangHunan 421001China

Ferroptosis is a form of regulated cell death characterized by iron-dependent overaccumulation of lipid peroxides,which causes membrane damage and cell *** can be prevented by cellular antioxidant mechanisms such as glutathione peroxidase 4(GPX4)-mediated elimination of the lipid peroxides at the cost of glutathione(GSH).As the rate-limiting step of GSH synthesis,the availability of intracellular cystine is controlled by the cell membrane-located cystine/glutamate antiporter system xc−.Indeed,the initially identified small molecule inducers of ferroptosis,RSL3 and erastin,turned out to be inhibitors of GPX4 and system xc−,respectively.

关键词： system initially limiting

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Safety and efficacy of thalidomide in patients with transfusiondependentβ-thalassemia:a randomized clinical trial

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Signal Transduction and Targeted Therapy 2021年第12期6卷 3723-3729页

作者： Jiang-Ming chen Wei-Jian zhu Jie liu Gui-Zhen Wang Xiao-Qin chen Yun Tan Wei-Wei Xu li-Wei Qu jin-Yan li Huan-Ju Yang Lan Huang Ning Cai Wei-Da Wang Ken Huang Jian-Quan Xu guo-Hui li Sheng He Tian-Ying Luo Yi Huang Song-Hua liu Wen-Qiang Wu Qi-Yang Lu Mei-guang zhou Shu-Ying chen Rong-Lan li Mei-ling Hu Ying Huang jin-Hua Wei Jun-Min li sai-juan chen guang-Biao zhou Department of hematology Wuzhou Gongren HospitalWuzhou 543001 GuangxiChina Department of hematology Zhuhai People’s Hospital(Zhuhai Hospital Affiliated with Jinan University)Zhuhai 541000 GuangdongChina state key laboratory of Molecular Oncology National Cancer Center/National Clinical Research Center for Cancer/Cancer HospitalChinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing 100021China Department of Reproductive medicine The First Affiliated Hospital of Hebei North UniversityZhangjiakou 075000 HebeiChina state key laboratory of Oncology in South china Collaborative Innovation Center for Cancer MedicineMedical Oncology DepartmentSun Yat-Sen University Cancer CenterGuangzhou 510060 GuangdongChina state key laboratory of medical genomics Shanghai Institute of HematologyNational Research Center for Translational MedicineRuijin Hospital Affiliated with Shanghai Jiao Tong University School of MedicineShanghai 200025China state key laboratory of Membrane Biology Institute of ZoologyChinese Academy of Sciences&University of Chinese Academy of SciencesBeijing 100101China Department of Pediatrics Affiliated Hospital of Youjiang Medical University for NationalitiesBaise City 533000 GuangxiChina Department of hematology Yulin Guinan HospitalYulin 537005 GuangxiChina Department of neurology Wuzhou Gongren HospitalWuzhou 543001 GuangxiChina guangxi key laboratory of Basic Research on Birth Defects Prevention and Treatment Guangxi Zhuang Autonomous Region Women and Children Health Care HospitalNanning 530000 GuangxiChina Department of hematology Guigang People’s HospitalGuigang 537100 GuangxiChina Department of hematology Hospital of Traditional Chinese Medicine of Wuzhou CityWuzhou 543002 GuangxiChina Department of hematology Wuzhou Red Cross HospitalWuzhou 543002 GuangxiChina Department of hematology Hechi People’s HospitalHechi City 547000 GuangxiChina

Thalidomide inducesγ-globin expression in erythroid progenitor cells,but its efficacy on patients with transfusion-dependentβ-thalassemia(TDT)remains *** this phase 2,multi-center,randomized,double-blind clinical trial,we aimed to determine the safety and efficacy of thalidomide in TDT patients.A hundred patients of 14 years or older were randomly assigned to receive placebo or thalidomide for 12 weeks,followed by an extension phase of at least 36 *** primary endpoint was the change of hemoglobin(Hb)level in the *** secondary endpoints included the red blood cell(RBC)units transfused and adverse *** the placebo-controlled period,Hb concentrations in patients treated with thalidomide achieved a median elevation of 14.0(range,2.5 to 37.5)g/L,whereas Hb in patients treated with placebo did not significantly *** the 12 weeks,the mean RBC transfusion volume for patients treated with thalidomide and placebo was 5.4±5.0 U and 10.3±6.4 U,respectively(P1).Adverse events of drowsiness,dizziness,fatigue,pyrexia,sore throat,and rash were more common with thalidomide than *** the extension phase,treatment with thalidomide for 24 weeks resulted in a sustainable increase in Hb concentrations which reached 104.9±19.0 g/L,without blood *** increase in Hb concentration and reduction in RBC transfusions were associated with nonβ0/β0 and HBS1L-MYB(rs9399137 C/T,C/C;rs4895441 A/G,G/G)*** results demonstrated that thalidomide is effective in patients with TDT.

关键词： transfusion patients thalidomide

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