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Haploidentical hematopoietic cell transplantation with or without an unrelated cord blood unit for adult acute myeloid leukemia:a multicenter,randomized,open-label,phase 3 trial

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Signal Transduction and Targeted Therapy 2024年第6期9卷 2669-2678页

作者： Biqi Zhou Jia Chen Tianhui Liu Yishan Ye Yanming Zhang Yiyang Ding Hong Liu MingQing Zhu Xiao Ma Xiaoli Li Longfei Zhao Zhihong Lin He Huang Yang Xu Depei Wu National Clinical Research Center for Hematologic Diseases Jiangsu Institute of HematologyThe First Affiliated Hospital of Soochow UniversitySuzhouChina Institute of Blood and marrow transplantation Collaborative Innovation Center of HematologySoochow UniversitySuzhouChina bone marrow transplantation Center The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiangChina department of hematology The Affiliated Huai’an Hospital of Xuzhou Medical University and The Second People’s Hospital of Huai’anHuai’anChina Soochow Hopes hematology Hospital SuzhouChina department of hematology Hygeia Suzhou Yongding HospitalSuzhouChina

Coinfusion of unrelated cord blood(UCB)units in haploidentical hematopoietic cell transplantation(haplo-HCT)(haplo-cord HCT)for hematopoietic malignancies showed promising results in previous reports,but the efficiency of haplo-cord HCT in acute myeloid leukemia(AML)still lacks sufficient *** multicenter,randomized,phase 3 trial(*** NCT03719534)aimed to assess the efficacy and safety of haplo-cord HCT in AML patients.A total of 268 eligible patients aged 18-60 years,diagnosed with measurable residual disease in AML(excluding acute promyelocytic leukemia),with available haploidentical donors and suitable for allotransplantation,were randomly allocated(1:1)to receive haplo-cord HCT(n=134)or haplo-HCT(n=134).The 3-year overall survival(OS)was the primary endpoint in this *** median follow-up was 36.50 months(IQR 24.75-46.50).The 3-year OS of Haplo-cord HCT group was better than haplo-HCT group(80.5%,95%confidence interval[CI]:73.7-87.9 vs.67.8%95%CI 60.0-76.5,p=0.013).Favorable progression-free survival(70.3%,95%CI 62.6-78.8 vs.57.6%,95%CI 49.6-67.0,p=0.012)and cumulative incidence of relapse(12.1%,95%CI 12.0-12.2 vs.30.3%,95%CI 30.1-30.4,p=0.024)were observed in haplo-cord HCT *** 3-4 adverse events(AEs)within two years posttransplantation in the two groups were ***-cord HCT patients exhibited a faster cumulative incidence of neutrophil recovery(p=0.026)and increased T-cell reconstitution in the early period ***-cord HCT can improve OS in AML patients without excessive AEs,which may exert additional benefits for recipients of haplo-HCT.

关键词： hematopoietic acute phase

PD-1^(+)and TIM-3^(+)T cells widely express commonγ-chain cytokine receptors in multiple myeloma patients,and IL-2,IL-7,IL-15 stimulation up-regulates PD-1 and TIM-3 on T cells

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Oncology Research 2024年第10期32卷 1575-1587页

作者： EGOR V.BATOROV ALISA D.INESHINA TATIANA A.ARISTOVA VERA V.DENISOVA SVETLANA A.SIZIKOVA DARIA S.BATOROVA GALINA Y.USHAKOVA EKATERINA Y.SHEVELA ELENA R.CHERNYKH Laboratory of Cellular Immunotherapy Research Institute of Fundamental and Clinical ImmunologyNovosibirsk630099Russia V.Zelman Institute of Medicine and Psychology Novosibirsk National Research State UniversityNovosibirsk630090Russia department of hematology and bone marrow transplantation Research Institute of Fundamental and Clinical ImmunologyNovosibirsk630099Russia

Background:Immune checkpoint ligand-receptor interactions appear to be associated with multiple myeloma(MM)***,previous studies showed the possibility of PD-1 and TIM-3 expression on T cells upon stimulation with commonγ-chain family cytokines in vitro and during homeostatic *** aim of the present work was to study the impact of homeostatic proliferation on the expansion of certain T cell subsets upregulating PD-1 and TIM-3 checkpoint ***:The expression of CD25,CD122,CD127 commonγ-chain cytokine receptors,phosphorylated signal transducer and activator of transcription-5(pSTAT5)and eomesodermin(EOMES)was comparatively assessed with flow cytometry in PD-1-and TIM-3-negative and positive T cells before the conditioning and during the first post-transplant month in peripheral blood samples of MM ***:Substantial proportions of PD-1-and TIM-3-positive T lymphocytes expressed commonγ-chain cytokine receptors and *** of cytokine receptor expressing cells were significantly higher within TIM-3+T cells compared to PD-1+TIM-3−*** proportions of both PD-1-/TIM-3-negative and positive CD8+T cells express EOMES,while only moderate frequencies of CD4+PD-1+/TIM-3+T cells up-regulate this transcription ***,the surface presence of CD25 and intranuclear expression of EOMES in CD4+T cells were mutually exclusive regardless of PD-1 and TIM-3 *** stimulation with commonγ-chain cytokines up-regulates PD-1 and TIM-3 during the proliferation of initially PD-1/TIM-3-negative T cells but fails to expand initially PD-1+and TIM-3+T cell subsets in ***:Both PD-1 and TIM-3 expressing T cells appear to be able to respond to homeostatic cytokine *** in commonγ-chain cytokine receptor expression between PD-1+and TIM-3+T cells may reflect functional dissimilarity of these cell *** blockade appears to alleviate lymphopenia-induced prolif

关键词： Autologous hematopoietic stem cell transplantation(AHSCT) CD25 CD122 Eomesodermin(EOMES) Homeostatic proliferation

PRC2 primes bivalent genes for transcription induction independent of histone methyltransferase activity

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Science China(Life Sciences) 2024年第9期67卷 2033-2035页

作者： Meihan Gong Ye Yuan Zhongye Dai Xuejiao Lv Jiacheng Su Dawei Huo Lin Niu Xu Chen Xudong Wu State Key Laboratory of Experimental hematology The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical EpigeneticsKey Laboratory of Immune Microenvironment and Disease(Ministry of Education)Department of Cell BiologySchool of Basic Medical SciencesTianjin Medical UniversityTianjin 300070China bone marrow transplantation Center the First Affiliated HospitalZhejiang University School of MedicineLiangzhu LaboratoryInstitute of HematologyZhejiang UniversityHangzhou 311113China

Dear Editor,Polycomb group proteins,conserved epigenetic transcriptional repressors,are crucial for orchestrating diverse developmental gene expression programs(Schuettengruber et al.,2017).The polycomb repressive complex 2(PRC2)catalyzes H3 lysine-27 trimethylation(H3K27me3)to establish a delicate balance with H3K4me3,forming a bivalent chromatin state at target gene promoters and thereby poising them for subsequent transcription activation(Bernstein et al.,2006).

关键词： valent thereby subsequent

Insights from TARGET-seq:Inflammation drives TP53-mediated clonal evolution

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The Innovation 2024年第2期5卷 7-8页

作者： Yeqian Zhao Wenxuan Huo Yue Liang Xiaodong Mo Shanshan Pei Yanmin Zhao bone marrow transplantation Center the First Affiliated HospitalZhejiang University School of MedicineHangzhou 310009China Liangzhu Laboratory Zhejiang University Medical CenterHangzhou 311121China Institute of hematology Zhejiang UniversityHangzhou 311121China Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing 100044China

Approximately 10%–20%myeloproliferative neoplasms(MPNs)can progress into blast-phase MPNs,also termed secondary acute myeloid leukemias(sAMLs),presenting dismal *** exhibits a distinctive clinical and pathological profile compared to de novo AML,marked by a higher incidence of erythroid leukemias and reduced responsive to conventional chemotherapies,resulting in a median survival of approximately 6 ***53 alterations are prevalent adverse events in leukemic transformation(LT),occurring in around one-third of sAML subjects.

关键词： TP53 neoplasms alterations

Establishment of a humanized mouse model using steady-state peripheral blood-derived hematopoietic stem and progenitor cells facilitates screening of cancer-targeted T-cell repertoires

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Cancer Innovation 2024年第3期3卷 1-21页

作者： Yulin Xu Wei Shan Qian Luo Meng Zhang Dawei Huo Yijin Chen Honghu Li Yishan Ye Xiaohong Yu Yi Luo He Huang bone marrow transplantation Center The First Affiliated HospitalZhejiang University School of MedicineHangzhouChina Liangzhu Laboratory Zhejiang UniversityHangzhouChina Institute of hematology Zhejiang UniversityHangzhouChina Zhejiang Province Engineering Research Center for Stem Cell and Immunity Therapy HangzhouChina School of Medicine Zhejiang UniversityHangzhouChina

Background:Cancer-targeted T-cell receptor T(TCR-T)cells hold promise in treating cancers such as hematological malignancies and breast ***,approaches to obtain cancer-reactive TCR-T cells have been ***:Here,we developed a novel strategy to screen for cancer-targeted TCR-T cells using a special humanized mouse model with person-specific immune *** steady-state circulating hematopoietic stem and progenitor cells were expanded via three-dimensional culture of steady-state peripheral blood mononuclear cells,and then the expanded cells were applied to establish humanized *** human immune system was evaluated according to the kinetics of dendritic cells,monocytes,T-cell subsets,and *** fully stimulate the immune response and to obtain B-cell precursor NAML-6-and triple-negative breast cancer MDA-MB-231-targeted TCR-T cells,we used the inactivated cells above to treat humanized mice twice a day every 7 ***,human T cells were processed for TCRβ-chain(TRB)sequencing *** the repertoires had been constructed,features such as the fraction,diversity,and immune signature were ***:The results demonstrated an increase in diversity and clonality of T cells after *** preferential usage and features of TRBV,TRBJ,and the V–J combination were also *** stress also induced highly clonal Science and Technology,Grant/Award Number:2021C03010;Zhejiang Provincial Natural Science Foundation of China,Grant/Award Numbers:LTGY24H080003,LY21H080004 *** burden and survival analysis demonstrated that stress induction could significantly inhibit the growth of subsequently transfused live tumor cells and prolong the survival of the humanized ***:We constructed a personalized humanized mouse model to screen cancer-targeted TCR-T *** platform provides an effective source of cancer-targeted TCR-T cells and allows for the design of patient-specific engineered T cells.

关键词： cancer-targeted T-cell receptor T(TCR-T)cells circulating hematopoietic stem and progenitor cells(HSPCs) humanized mouse model steady-state peripheral blood T-cell receptorβ-chain(TRB) three-dimensional culture

The non-canonical poly(A)polymerase FAM46C promotes erythropoiesis

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Journal of Genetics and Genomics 2024年第6期51卷 594-607页

作者： Ke Yang Tiangi Zhu Jiaying Yin Qiaoli Zhangg Jing Li Hong Fan Gajing Han Weiyin Xu Nan Liu Xiang Lv bone marrow transplantation Center The First Affiliated HospitalZhejiang University School of MedicineHangzhouZhejiang 310003China Liangzhu Laboratory Zhejang UniversityHangzhouZhejang 311121China Institute of hematology Zhejiang UniversityHangzhouZhejiang 311121China The State Key Laboratory for Complex Severeand Rare DiseasesHaihe Laboratory of Cell EcosystemDepartment of PathophysiologyInstitute of Basic Medical SciencesChinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China Medical Epigenetics Research Center Chinese Academy of Medical Sciences&Peking Union Medical CollegeBeijing 100005China

The post-transcriptional regulation of mRNA is a crucial component of gene *** disruption of this process has detrimental effects on the normal development and gives rise to various *** for novel post-transcriptional regulators and exploring their roles are essential for understanding development and *** a multimodal analysis of red blood cell trait genome-wide association studies(GWAS)and transcriptomes of erythropoiesis,we identify FAM46C,a non-canonical RNA poly(A)polymerase,as a necessary factor for proper red blood cell ***46C is highly expressed in the late stages of the erythroid lineage,and its developmental upregulation is controlled by an erythroidspecific *** demonstrate that FAM46C stabilizes mRNA and regulates erythroid differentiation in a polymerase activity-dependent ***,we identify transcripts of lysosome and mitochondria components as highly confident in vivo targets of FAM46C,which aligns with the need of maturing red blood cells for substantial clearance of organelles and maintenance of cellular redox *** conclusion,our study unveils a unique role of FAM46C in positively regulating lysosome and mitochondria components,thereby promoting erythropoiesis.

关键词： FAM46C TENT5C Poly(A)polymerase Erythroblasts Post-transcriptional regulation Erythroid-specific enhancer

Lymph node-biomimetic scaffold boosts CAR-T therapy against solid tumor

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National Science Review 2024年第4期11卷 206-215页

作者： Ziyan Liao Jie Jiang Wei Wu Jiaqi Shi Yanfang Wang Yuejun Yao Tao Sheng Feng Liu Wei Liu Peng Zhao Feifei Lv Jie Sun Hongjun Li Zhen Gu National Key Laboratory of Advanced Drug Delivery and Release Systems College of Pharmaceutical Sciences Zhejiang University Key Laboratory of Advanced Drug Delivery Systems of Zhejiang Province College of Pharmaceutical SciencesZhejiang University Liangzhu Laboratory Zhejiang University bone marrow transplantation Center of the First Affiliated Hospital and department of Cell Biology Zhejiang University School of Medicine department of Medical Oncology The First Affiliated Hospital School of Medicine Zhejiang University department of Laboratory Medicine The First Affiliated Hospital Zhejiang University School of Medicine department of Hepatobiliary and Pancreatic Surgery The Second Affiliated HospitalSchool of MedicineZhejiang University Jinhua Institute of Zhejiang University MOE Key Laboratory of Macromolecular Synthesis and Functionalization of Ministry of Education Department of Polymer Science and EngineeringZhejiang University department of General Surgery Sir Run Run Shaw Hospital School of Medicine Zhejiang University

The limited infiltration and persistence of chimeric antigen receptor(CAR)-T cells is primarily responsible for their treatment deficits in solid tumors. Here, we present a three-dimensional scaffold, inspired by the physiological process of T-cell proliferation in lymph nodes. This scaffold gathers the function of loading,delivery, activation and expansion for CAR-T cells to enhance their therapeutic effects on solid tumors. This porous device is made from poly(lactic-co-glycolic acid) by a microfluidic technique with the modification of T-cell stimulatory signals, including anti-CD3, anti-CD28 antibodies, as well as cytokines. This scaffold fosters a 50-fold CAR-T cell expansion in vitro and a 15-fold cell expansion in vivo. Particularly, it maintains long-lasting expansion of CAR-T cells for up to 30 days in a cervical tumor model and significantly inhibits the tumor growth. This biomimetic delivery strategy provides a versatile platform of cell delivery and activation for CAR-T cells in treating solid tumors.

关键词： drug delivery cell therapy bioinspired biomaterials cancer immunotherapy

Azacitidine maintenance therapy for blastic plasmacytoid dendritic cell neoplasm allograft: A case report

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World Journal of Clinical Cases 2024年第1期12卷 136-141页

作者： Li-Li Tao Hui-Ting Wen Zi-Yi Wang Juan Cheng Li Zhao department of hematology The First Clinical Medical CollegeLanzhou UniversityLanzhou 730000Gansu ProvinceChina department of hematology The First Hospital of Lanzhou UniversityLanzhou 730000Gansu ProvinceChina

BACKGROUND Blastic plasmacytoid dendritic cell neoplasm(BPDCN)is a rare,highly invasive malignant *** is no universally accepted standard of care because of its rarity and the dearth of prospective *** is still challenging for some patients to achieve persistent clinical remission or cure,despite the success of allogeneic hematopoietic stem cell transplantation(allo-HSCT),indicating that there is still a significant recurrence *** report a case of prevention of BPDCN allograft recurrence by azacitidine maintenance therapy and review the relevant *** SUMMARY We report a 41-year-old man with BPDCN who was admitted to hospital due to skin sclerosis for>5 mo’*** was diagnosed by combined clinical assessment and laboratory *** diagnosis,the patients underwent induction consolidation chemotherapy to achieve the first complete remission,followed by bridging ***-transplantation,azacitidine(75 mg/m2 for 7 d)was administered as maintenance therapy,with repeat administration every 4–6 wk and appropriate extension of the chemotherapy *** 10 cycles,the patient has been disease free for 26 mo after *** assessments of bone marrow morphology,minimal residual disease,full donor chimerism,Epstein–Barr virus,and cytomegalovirus all yielded normal results with no abnormalities *** Azacitidine may be a safe and effective maintenance treatment for BPDCN following transplantation because there were no overt adverse events during the course of treatment.

关键词： Blastic plasmacytoid dendritic cell neoplasm Azacitidine Allogeneic hematopoietic stem cell transplantation Maintenance therapy Case report

Aptamer-Based Cell-Surface Profiling with Single-Cell Resolution Enables Precise Cancer Characterization

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CCS Chemistry 2024年第1期6卷 196-207页

作者： Liujun Xu Yawei Feng Tong Wang Shenhuan Li Kangli Xu Yue Sun Yi Luo Yishan Ye Yan Miao Yun Dong Zhenzhen Guo Qing Zhang Benshang Li He Huang Xue-Qiang Wang Liping Qiu Weihong Tan Molecular Science and Biomedicine Laboratory State Key Laboratory of Chemo/Biosensing and ChemometricsCollege of Chemistry and Chemical EngineeringCollege of BiologyAptamer Engineering Center of Hunan ProvinceHunan UniversityChangshaHunan 410082 The Key Laboratory of Zhejiang Province for Aptamers and Theranostics Zhejiang Cancer HospitalHangzhou Institute of MedicineChinese Academy of SciencesHangzhouZhejiang 310022 Institute of Molecular Medicine Renji HospitalShanghai Jiao Tong University School of MedicineCollege of Chemistry and Chemical EngineeringShanghai Jiao Tong UniversityShanghai 200240 bone marrow transplantation Center The First Affiliated HospitalSchool of MedicineZhejiang UniversityHangzhou 310003 Institute of hematology Zhejiang UniversityHangzhou 310003 department of hematology and Oncology Shanghai Children’s Medical CenterShanghai Jiao Tong University School of MedicineShanghai Jiao Tong UniversityShanghai 200127

Molecular profiling of cell-surface proteins is a powerful strategy for precise cancer *** mass cytometry(MC)enables synchronous detection of over 40 cellular parameters,its full potential in disease classification is challenged by the limited types of recognition probes currently *** this work,we synthesize a panel of heavy isotopeconjugated aptamers to profile cancer-associated signatures on the surface of hematological malignancy(HM)*** on 15 molecular signatures,we performed cell-surface profiling that allowed the precise classification of 8 HM cell *** with machine-learning technology,this aptamer-based MC platform also achieved multiclass identification of HM subtypes in clinical sampleswith 100%accuracy in the training cohort and 80%accuracy in the test ***,we report an effective and practical strategy for precise cancer classification at the singlecell level,paving the way for its clinical use in the near future.

关键词： molecular profiling cancer diagnosis mass cytometry aptamers machine learning