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Glucocorticoid and glycolysis inhibitors cooperatively abrogate acute graft-versus-host disease

Science China(Life Sciences) 2023年第3期66卷 528-544页

作者： Qi Wen Zheng-Li xu Yu Wang Meng Lv Yang Song Zhong-Shi Lyv Tong Xing lan-ping xu Xiao-Hui Zhang Xiao-Jun Huang Yuan Kong Peking University People's Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationCollaborative Innovation Center of HematologyPeking UniversityBeijing 100044China Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100044China

Although glucorticosteroids(GCs)are the standard first-line therapy for acute graft-versus-host disease(a Gv HD),nearly 50%of a Gv HD patients have no response to *** role of T cell metabolism in murine a Gv HD was recently ***,whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate a Gv HD remains to be *** glycolysis,characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3(PFKFB3),and higher rates of glucose consumption and lactate production were found in Tcells from a Gv HD *** upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory *** a humanized mouse model,PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented a Gv HD,***,our integrated data from patient samples in vitro,in a humanized xenogeneic murine model of a Gv HD and graft-versus-leukaemia(GVL)demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate a Gv HD without loss of GVL ***,the current study indicated that glycolysis is critical for T cell activation and induction of human a Gv ***,the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for a Gv HD *** combined with glycolysis inhibitors promises to be a novel first-line combination therapy for a Gv HD patients.

关键词： allogeneic haematopoietic stem cell transplantation graft versus host disease human T cells glycolysis

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Repair of dysfunctional bone marrow endothelial cells alleviates aplastic anemia

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Science China(Life Sciences) 2023年第11期66卷 2553-2570页

作者： Shu-Qian Tang Tong Xing Zhong-Shi Lyu Li-ping Guo Mi Liang Chen-Yuan Li Yuan-Yuan Zhang Yu Wang lan-ping xu Xiao-Hui Zhang Xiao-Jun Huang Yuan Kong Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationCollaborative Innovation Center of HematologyPeking UniversityBeijing 100044China Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100871China

Aplastic anemia(AA)is a life-threatening disease characterized by bone marrow(BM)failure and *** an important component of the BM microenvironment,endothelial cells(ECs)play a crucial role in supporting hematopoiesis and regulating ***,whether impaired BM ECs are involved in the occurrence of AA and whether repairing BM ECs could improve hematopoiesis and immune status in AA remain *** this study,a classical AA mouse model and VE-cadherin blocking antibody that could antagonize the function of ECs were used to validate the role of BM ECs in the occurrence of ***-L-cysteine(NAC,a reactive oxygen species scavenger)or exogenous EC infusion was administered to AA ***,the frequency and functions of BM ECs from AA patients and healthy donors were *** ECs from AA patients were treated with NAC in vitro,and then the functions of BM ECs were *** found that BM ECs were significantly decreased and damaged in AA *** failure and immune imbalance became more severe when the function of BM ECs was antagonized,whereas NAC or EC infusion improved hematopoietic and immunological status by repairing BM ECs in AA ***,BM ECs in AA patients were decreased and ***,dysfunctional BM ECs in AA patients led to their impaired ability to support hematopoiesis and dysregulate T cell differentiation toward proinflammatory phenotypes,which could be repaired by NAC in *** reactive oxygen species pathway was activated,and hematopoiesis-and immune-related signaling pathways were enriched in BM ECs of AA *** conclusion,our data indicate that dysfunctional BM ECs with impaired hematopoiesis-supporting and immunomodulatory abilities are involved in the occurrence of AA,suggesting that repairing dysfunctional BM ECs may be a potential therapeutic approach for AA patients.

关键词： aplastic anemia endothelial cell N-acetyl-L-cysteine hematopoietic stem cell T cell

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Haploidentical stem cell transplantation in patients with chronic myelomonocytic leukemia

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Science China(Life Sciences) 2020年第8期63卷 1261-1264页

作者： Yu-Qian Sun Chen Zhao Yu Wang Chen-Hua Yan Xiao-Hui Zhang lan-ping xu Kai-Yan Liu Xiao-Jun Huang Peking University People’s Hospital Peking University Institute of HaematologyNational Clinical Research Center for Hematologic diseaseBeijing Key Laboratory of Haematopoietic Stem Cell TransplantationBeijing 100044China Peking-Tsinghua Centre for Life Sciences Beijing 100871China

Dear Editor,Chronic myelomonocytic leukemia (CMML) is a rare clonal hematological malignancy with both myelodysplastic and myeloproliferative features. Patients with CMML have a very poor prognosis。

关键词： leukemia prognosis patients

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Pre-transplantation cytoreduction does not benefit advancedmyelodysplastic syndrome patients after myeloablative transplantation with grafts from family donors

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Cancer Communications 2021年第4期41卷 333-344页

作者： Yu-Qian Sun lan-ping xu Kai-Yan Liu Xiao-Hui Zhang Chen-Hua Yan Jian Jin Xiao-Jun Huang Yu Wang Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic Disease BeijingKey Laboratory of Hematopoietic Stem Cell TransplantationBeijing 100044P.R.China Peking-Tsinghua Center for Life Sciences Beijing 100871P.R.China Collaborative Innovation Center of Hematology Peking UniversityBeijing 100871P.R.China

Background:The role of pre-hematopoietic stem cell transplantation(HSCT)cytoreduction with either induction chemotherapy(IC)or hypomethylating agents(HMAs)in treating advanced myelodysplastic syndrome(MDS)remains *** aimed to evaluate pre-HSCT strategies by comparing the endpoints related to disease control between advanced MDS patients with pre-HSCT cytoreduction and those with best supportive ***:We described 228 consecutive advanced MDS patients who received HSCT from a haploidentical donor(HID,n=162)or matched related donor(MSD,n=66)with uniform myeloablative conditioning regimens between January 2015 and December *** these 228 patients,131(57.5%)were treated exclusively with pre-HSCT best supportive care(BSC),49(22.5%)were given HMA,and 48(21.1%)received both IC and *** score-matching analysis,multivariate analyses,and subgroup analyses were performed to elucidate the impact of pre-HSCT strategies on transplant ***:The 3-year relapse-free survival(RFS)rates were 78.2% and 70.0% for the BSC and cytoreduction cohorts(P=0.189)and were 78.2%,66.7%,and 73.2% for the BSC,HMA,and HMA+IC groups,respectively(P=0.269).A propensity score-matching analysis confirmed that the 3-year RFS rates were 81.9%,87.5%,and 66.9% for BSC,cytoreduction complete remission(CR),and cytoreduction non-CRgroups,respectively(P=0.051).Multivariate analyses demonstrated that pre-HSCT cytoreduction,older patient age,monosomal karyotype,and interval between diagnosis and HSCT were poor prognostic factors for *** the subgroup analyses,BSC was associated with longer RFS compared to cytoreduction among the younger patients,those with international prognostic scoring system intermediate-2/high risk at diagnosis,and those with intermediate/poor ***:Different pre-HSCT therapies did not yield discrepant post-HSCT *** benefit in terms of post-HSCT outcomes were correlated with pre-HSCT cytoreduction in advanced MDS even for cyt

关键词： myelodysplastic syndrome cytoreduction hypomethylating agent induction chemotherapy hematopoietic stem cell transplantation best supportive care

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The role of collateral related donors in haploidentical hematopoietic stem cell transplantation

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Science Bulletin 2018年第20期63卷 1376-1382页

作者： Xiao-Dong Mo Yuan-Yuan Zhang Xiao-Hui Zhang lan-ping xu Yu Wang Chen-Hua Yan Huan Chen Yu-Hong Chen Ying-Jun Chang Kai-Yan Liu Xiao-Jun Huang Peking University People's Hospital Peking University Institute of hematologyBeijing 100044China Peking-Tsinghua Center for Life Sciences Beijing 100871China Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation Beijing 100044China

A key issue in the haploiedntical hematopoietic stem cell transplantation(haplo-HSCT) setting is the search for the best donor, because donor selection can significantly impact the clinical outcomes. We aimed to identify the role of collateral related donors(CRDs) in donor selection for haplo-HSCT through comparing the clinical outcomes between CRDs(n = 60) and maternal donors(MDs, n = 296), which were the last choice of donor selection in immediate related donors(IRDs). The cumulative incidence of graft-versus-host disease was comparable between CRDs and MDs. The 5-year cumulative incidence of relapse and non-relapse mortality was 22.0%(95% CI, 11.3%–32.7%) versus 17.4%(95% CI, 13.0%–21.8%)(P = 0.455) and 25.0%(95% CI, 13.9%–36.1%) versus 23.1%(95% CI, 18.2%–28.0%)(P = 0.721) for the CRDs and MDs, respectively. The 5-year probabilities of disease-free survival and overall survival was 53.2%(95% CI, 40.4%–66.0%) versus 59.5%(95% CI, 53.8%–65.2%)(P = 0.406) and 56.5%(95% CI,43.8%–69.2%) versus 61.8%(95% CI, 56.1%–67.5%)(P = 0.458) for the CRDs and MDs, *** donor/male recipient(FDMR) CRDs were associated with the poorest clinical outcomes, and the clinical outcomes of non-FDMR CRDs were comparable to those of MDs. In summary, our results showed that CRDs did not showed superiority over MDs. Thus, IRDs should be the first choice of donor selection, and CRDs could only be the donors for those without IRDs.

关键词： Haploidentical Hematopoietic stem cell transplantation Collateral related donors Paternal donors Maternal donors

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M2 macrophages,but not Ml macrophages,support megakaryopoiesis by upregulating PI3K-AKT pathway activity

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Signal Transduction and Targeted Therapy 2021年第7期6卷 2196-2209页

作者： Hong-Yan Zhao Yuan-Yuan Zhang Tong Xing Shu-Qian Tang Qi Wen Zhong-Shi Lyu Meng Lv Yu Wang lan-ping xu Xiao-Hui Zhang Yuan Kong Xiao-Jun Huang Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationCollaborative Innovation Center of HematologyPeking UniversityBeijingChina Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijingChina

Dysfunctional megakaryopoiesis hampers platelet production,which is closely associated with thrombocytopenia(PT).Macrophages(MΦs)are crucial cellular components in the bone marrow(BM)***,the specific effects of M1 MΦs or M2 MΦs on regulating megakaryocytes(MKs)are largely *** the current study,aberrant BM-M1/M2 MO polarization,characterized by increased M1 MΦs and decreased M2 MΦs and accompanied by impaired megakaryopoiesis-supporting abilities,was found in patients with PT ***-seq and western blot analysis showed that the PI3K-AKT pathway was downregulated in the BM MΦs of PT ***,in vitro treatment with PI3K-AKT activators restored the impaired megakaryopoiesis-supporting ability of MΦs from PT ***,we found M1 MΦs suppress,whereas M2 MCDs support MK maturation and platelet formation In *** inhibition of PI3K-AKT pathway reduced megakaryopoiesis-supporting ability of M2 MΦs,as indicated by decreased MK count,colony-forming unit number,high-ploidy distribution,and platelet ***,genetic knockdown of the PI3K-AKT pathway impaired the megakaryopoiesis-supporting ability of MΦs both in vitro and in a MO-specific PI3K-knockdown murine model,indicating a critical role of PI3K-AKT pathway in regulating the megakaryopoiesis-supporting ability of M2 M(***,our preliminary data indicated that TGF-β released by M2 MΦs may facilitate megakaryopoiesis through upregulation of the JAK2/STAT5 and MAPK/ERK pathways in *** together,our data reveal that M1 and M2 MΦs have opposing effects on MKs in a PI3K-AKT pathway-dependent manner,which may lead to new insights into the pathogenesis of thrombocytopenia and provide a potential therapeutic strategy to promote megakaryopoiesis.

关键词： PI3K impaired supporting

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Expanded clinical-grade NK cells exhibit stronger effects than primary NK cells against HCMV infection

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Cellular & Molecular Immunology 2023年第8期20卷 895-907页

作者： Qian-Nan Shang Xing-Xing Yu Zheng-Li xu Yu-Hong Chen Ting-Ting Han Yuan-Yuan Zhang Meng Lv Yu-Qian Sun Yu Wang lan-ping xu Xiao-Hui Zhang Xiang-Yu Zhao Xiao-Jun Huang Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationPeking UniversityBeijingChina Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijingChina

Cytomegalovirus (CMV) reactivation remains a common complication and leads to high mortality in patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). Early natural killer (NK) cell reconstitution may protect against the development of human CMV (HCMV) infection post-HSCT. Our previous data showed that ex vivo mbIL21/4-1BBL-expanded NK cells exhibited high cytotoxicity against leukemia cells. Nevertheless, whether expanded NK cells have stronger anti-HCMV function is unknown. Herein, we compared the anti-HCMV functions of ex vivo expanded NK cells and primary NK cells. Expanded NK cells showed higher expression of activating receptors, chemokine receptors and adhesion molecules;stronger cytotoxicity against HCMV-infected fibroblasts;and better inhibition of HCMV propagation in vitro than primary NK cells. In HCMV-infected humanized mice, expanded NK cell infusion resulted in higher NK cell persistence and more effective tissue HCMV elimination than primary NK cell infusion. A clinical cohort of 20 post-HSCT patients who underwent adoptive NK cell infusion had a significantly lower cumulative incidence of HCMV infection (HR = 0.54, 95% CI = 0.32–0.93, p = 0.042) and refractory HCMV infection (HR = 0.34, 95% CI = 0.18–0.65, p = 0.009) than controls and better NK cell reconstitution on day 30 post NK cell infusion. In conclusion, expanded NK cells exhibit stronger effects than primary NK cells against HCMV infection both in vivo and in vitro.

关键词： Allogeneic haematopoietic stem cell transplantation Natural killer cells Human cytomegalovirus infection Adoptive infusion

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Catalytic detoxification of mitoxantrone by graphitic carbon nitride(g-C_(3)N_(4))supported Fe/Pd bimetallic nanoparticles

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Journal of Environmental Sciences 2025年第2期148卷 614-624页

作者： Qianyu xu Haoyang Fu Jiyuan Gu Liyu Lei lan Ling State Key Laboratory for Pollution Control and Resource Reuse College of Environmental Science and EngineeringTongji UniversityShanghai 200092China

The overuse of antibiotics and antitumor drugs has resulted in more and more extensive pollution of water bodies with organic drugs,causing detrimental ecological effects,which have attracted attention towards effective and sustainable methods for antibiotics and antitumor drug ***,the hybrid nanomaterial(g-C_(3)N_(4)@Fe/Pd)was synthesized and used to remove a kind of both an antibiotic and antitumor drug named mitoxantrone(MTX)with 92.0%removal efficiency,and the MTX removal capacity is 450 mg/*** exposing to the hybrid material the MTX aqueous solution changed color from dark blue to lighter progressively,and LC-UV results of residual solutions showthat a newpeak at 3.0min(MTX:13.2min)after removal by g-C_(3)N_(4)@Fe/Pd appears,with the simultaneous detection of intermediate products indicating that g-C_(3)N_(4)@Fe/Pd indeed degrades *** mass spectrometric analysis suggests that the nuclear mass ratio decreased from 445.2(M+1H)to 126.0(M+1H),169.1(M+1H),239.2(M+1H),267.3(M+1H),285.2(M+1H),371.4(M+1H)and 415.2(M+1H),and the maximum proportion(5.63%)substance of all degradation products(126.0(M+1H))is 40-100 times less toxic than MTX.A mechanism for the removal and degradation of mitoxantrone was ***,actual water experiments confirmed that the maximum removal capacity of MTX by g-C_(3)N_(4)@Fe/Pd is up to 492.4 mg/g(0.02 g/L,10 ppm).

关键词： Degradation LC-QTOF-MS Nanoparticles Mitoxantrone Aqueous solution

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Impact of prophylactic/preemptive donor lymphocyte infusion and intensified conditioning for relapsed/refractory leukemia:a real-world study

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Science China(Life Sciences) 2020年第10期63卷 1552-1564页

作者： Yu Wang Qi-Fa Liu De-Pei Wu Jing-Bo Wang Xi Zhang Heng-Xiang Wang Feng Gao Shun-Qing Wang Zi-Min Sun Jian Ouyang Kai-Lin xu Su-Jun Gao lan-ping xu Chen-Hua Yan Xiao-Jun Huang Department of Hematology Peking University People’s HospitalPeking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing 100044China Department of Hematology Nanfang HospitalSouthern Medical UniversityGuangzhou 510515China Department of Hematology the First Affiliated Hospital of Soochow UniversitySuzhou 215006China Department of Hematology Aero Center Space HospitalBeijing 100049China Department of Hematology Xinqiao HospitalThird Military Medical UniversityChongqing 400037China Department of Hematology Air Force General HospitalPLABeijing 100142China Department of Hematology the Affiliated Hospital of North China University Science and TechnologyTangshan 063210China Department of Hematology Guangzhou First People’s HospitalGuangzhou 510180China Department of Hematology Anhui Provincial HospitalHefei 230001China Department of Hematology Nanjing Drum Tower HospitalThe Affiliated Hospital of Nanjing University Medical SchoolNanjing 210008China Department of Hematology the Affiliated Hospital of Xuzhou Medical UniversityXuzhou 221000China Department of Hematology the First Affiliated Hospital of Jilin UniversityChangchun 130021China Peking-Tsinghua Center for Life Sciences Beijing 100871China Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies Chinese Academy of Medical Sciences2019RU029Beijing 100730China Collaborative Innovation Center of Hematology Beijing 100044China

Prophylactic/preemptive donor lymphocyte infusion(p/pDLI)and intensified conditioning have shown promising results in experimental studies of refractory/relapsed acute leukemia(RRAL),but real-world data remain *** conducted a multicenter,population-based analysis of 932 consecutive *** three-year leukemia-free survival(LFS)rates were 56%for patients receiving both p/pDLI and intensified myeloablative conditioning(MAC)(intenseMAC)and 30%for those who received neither therapy per landmark *** analyses were run separately for acute myeloid leukemia(AML)and acute lymphoblastic leukemia(ALL),and p/pDLI treatment was linked to significantly higher LFS than non-DLI for both AML and ALL patients without increasing the nonrelapse *** was associated with significantly lower relapse and higher LFS than nonintensified MAC despite higher nonrelapse mortality rates in ALL,while there was no impact of intenseMAC observed in AML.p/pDLI achieved superior outcomes in both matched-sibling donor(MSD)and haploidentical donor transplantation,while intenseMAC only influenced MSD *** suggest that RRAL patients receiving“total therapy”by way of p/pDLI and intensified conditioning treatment have an improved chance for LFS,with p/pDLI being safer with a more extensive impact relative to *** with RRAL can tolerate both interventions and achieve a reasonable outcome.

关键词： donor lymphocyte infusion intensified conditioning refractory/relapsed leukemia haploidentical prophylactic

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Comparable anti-CMV responses of transplant donor and third-party CMV-specific T cells for treatment of CMV infection after allogeneic stem cell transplantation

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Cellular & Molecular Immunology 2022年第4期19卷 482-491页

作者： xu-Ying Pei xue-Fei Liu Xiang-Yu Zhao Meng Lv Xiao-Dong Mo Ying-Jun Chang Qian-Nan Shang Yu-Qian Sun Yu-Hong Chen lan-ping xu Yu Wang Xiao-Hui Zhang Kai-Yan Liu Xiao-Jun Huang Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing100044China Peking-Tsinghua Center for Life Sciences Beijing100871China

Adoptive transfer of cytomegalovirus(CMV)-specific cytotoxic T lymphocytes(CMV-CTLs)from original transplant donors or third-party donors was effective for the treatment of CMV infection after allogenic stem cell transplantation(allo-SCT),but the antiviral activity of CMV-CTL types has not been *** determine whether third-party CMV-CTLs provide comparable long-term antiviral efficacy to transplant donor CMV-CTLs,we first compared the antiviral abilities of transplant donors and third-party CMV-CTLs for treatment of CMV infection in two mouse models,compared the in vivo recovery of CMV-specific immunity,and analyzed the underlying mechanisms driving sustained antiviral *** results showed that both donor and third-party CMV-CTLs effectively combated systemic CMV infection by reducing CMV pathology and tumor burden 28 days *** in vivo recovery of CMV-specific immunity after CMV-CTL infusion was comparable in both groups.A detailed analysis of the source of recovered CMV-CTLs showed the proliferation and expansion of graft-derived endogenous CMV-CTLs in both *** clinical study,which enrolled 31 patients who received third-party CMV-CTLs and 62 matched pairs of individuals who received transplant donor CMV-CTLs for refractory CMV infection,further showed that adoptive therapy with donor or third-party CMV-CTLs had comparable clinical responses without significant therapy-related *** observed strong expansion of CD8+tetramer+T cells and proliferation of recipient endogenous CMV-CTLs after CMV-CTL infusion,which were associated with a reduced or cleared viral *** data confirmed that adoptive therapy with third-party or transplant donor CMV-CTLs triggered comparable antiviral responses to CMV infection that might be mediated by restoration of endogenous CMV-specific immunity.

关键词： Allogeneic stem cell transplantation CMV-specific cytotoxic T lymphocytes Transplant donor Third party donor Immunotherapy

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