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Ecological principle meets cancer treatment: treating children with acute myeloid leukemia with low-dose chemotherapy

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National Science Review 2019年第3期6卷 469-479页

作者： Yixin Hu Aili Chen Xinchang Zheng Jun Lu Hailong He Jin Yang Ya Zhang Pinpin Sui Jingyi Yang Fuhong He Yi Wang Peifang Xiao Xin Liu Yinmei Zhou Deqing Pei Cheng Cheng Raul C.Ribeiro Shaoyan Hu Qian-fei Wang Department of Hematology and Oncology Children's Hospital of Soochow University CAS Key Laboratory of Genomic and Precision Medicine Beijing Institute of Genomics Chinese Academy of Sciences University of Chinese Academy of Sciences Department of Pediatrics Nothern Jiangsu People's Hospital Department of Biostatistics St.Jude Children's Research Hospital Department of Oncology and Global Medicine International Outreach Program St.Jude Children's Research Hospital

Standard chemotherapy regimens for remission induction of pediatric acute myeloid leukemia(AML) are associated with significant morbidity and mortality. We performed a cohort study to determine the impact of reducing the intensity of remission induction chemotherapy on the outcomes of selected children with AML treated with a low-dose induction regimen plus granulocyte colony stimulating factor(G-CSF)(low-dose chemotherapy(LDC)/G-CSF). Complete response(CR) after two induction courses was attained in 87.0%(40/46) of patients receiving LDC/G-CSF. Post-remission therapy was offered to all patients, and included standard consolidation and/or stem cell transplantation. During the study period, an additional 94 consecutive children with AML treated with standard chemotherapy(SDC) for induction(80/94(85.1%) of the patients attained CR after induction Ⅱ, P = 0.953) and post-remission. In this non-randomized study, there were no significant differences in 4-year event-free(67.4 vs. 70.7%; P = 0.99)and overall(70.3 vs. 74.6%, P = 0.69) survival in the LDC/G-CSF and SDC cohorts, respectively. After the first course of induction, recovery of white blood cell(WBC) and platelet counts were significantly faster in patients receiving LDC/G-CSF than in those receiving SDC(11.5 vs. 18.5 d for WBCs(P < 0.001); 15.5 vs. 22.0 d for platelets(P < 0.001)). To examine the quality of molecular response, targeted deep sequencing was performed. Of 137 mutations detected at diagnosis in 20 children who attained hematological CR after two courses of LDC/G-CSF(n = 9) or SDC(n = 11), all of the mutations were below the reference value(variant allelic frequency <2.5%) after two courses, irrespective of the treatment group. In conclusion, children with AML receiving LDC/G-CSF appear to have similar outcomes and mutation clearance levels, but significantly lower toxicity than those receiving SDC. Thus, LDC/G-CSF should be further evaluated as an effective alternative to remission induction in pedia

关键词： low-dose chemotherapy acute myeloid leukemia G-CSF

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FGF13 suppresses acute myeloid leukemia by regulating bone marrow niches

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Frontiers of Medicine 2022年第6期16卷 896-908页

作者： Ran Li Kai Xue Junmin Li Shanghai Institute of Hematology State Key Laboratory of Medical GenomicsNational Research Center for Translational Medicine at ShanghaiRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai200025China

Fibroblast growth factor 13(FGF13)is aberrantly expressed in multiple cancer types,suggesting its essential role in ***,we aimed to explore its definite role in the development of acute myeloid leukemia(AML)and emphasize its associations with bone marrow *** showed that FGF13 was lowly expressed in patients with AML and that its elevated expression was related to prolonged overall survival(OS).Univariate and multivariate Cox regression analyses identified FGF13 as an independent prognostic factor.A prognostic nomogram integrating FGF13 and clinicopathologic variables was constructed to predict 1-,3-,and 5-year *** mutation and functional analyses indicated that FGF13 was not associated with AML driver mutations but was related to bone marrow *** for immunity,FGF13 was remarkably associated with T cell count,immune checkpoint genes,and *** addition,FGF13 overexpression substantially inhibited the growth and significantly induced the early apoptosis of AML *** xenograft study indicated that FGF13 overexpression prolonged the survival of recipient ***,FGF13 could serve as an independent prognostic factor for AML,and it was closely related to the bone marrow microenvironment.

关键词： acute myeloid leukemia FGF13 prognosis immune-related genes bone marrow niches

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Single-cell immune landscape of measurable residual disease in acute myeloid leukemia

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Science China(Life Sciences) 2024年第11期67卷 2309-2322页

作者： Xiaodong Mo Weilong Zhang Guomei Fu Yingjun Chang Xiaohui Zhang Lanping Xu Yu Wang Chenhua Yan Mengzhu Shen Qiuxia Wei Changjian Yan Xiaojun Huang Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing 100044China Department of Hematology Lymphoma Research CenterPeking University Third HospitalBeijing100191China Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100044China Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies Chinese Academy of Medical SciencesBeijing 100044China

Measurable residual disease(MRD)is a powerful prognostic factor of relapse in acute myeloid leukemia(AML).We applied the single-cell RNA sequencing to bone marrow(BM)samples from patients with(n=20)and without(n=12)MRD after allogeneic hematopoietic stem cell transplantation.A comprehensive immune landscape with 184,231 cells was *** with CD8+T cells enriched in the MRDnegative group(MRD‒_CD8),those enriched in the MRD-positive group(MRD+_CD8)showed lower expression levels of cytotoxicity-related *** monocyte clusters(i.e.,MRD+_M)and three B-cell clusters(i.e.,MRD+_B)were enriched in the MRD-positive *** from an MRD-positive state to an MRD-negative state was accompanied by an increase in MRD‒_CD8 clusters and vice *** cell clusters employed the macrophage migration inhibitory factor pathway to regulate MRD‒_CD8 *** findings revealed the characteristics of the immune cell landscape in MRD positivity,which will allow for a better understanding of the immune mechanisms for MRD conversion.

关键词： acute myeloid leukemia measurable residual disease immune landscape single-cell RNA sequencing allogeneic hematopoietic stem cell transplantation

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Transferrin-guided intelligent nanovesicles augment the targetability and potency of clinical PLK1 inhibitor to acute myeloid leukemia

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Bioactive Materials 2023年第3期21卷 499-510页

作者： Yifeng Xia Jingnan An Jiaying Li Wenxing Gu Yifan Zhang Songsong Zhao Cenzhu Zhao Yang Xu Bin Li Zhiyuan Zhong Fenghua Meng Biomedical Polymers Laboratory College of ChemistryChemical Engineering and Materials Scienceand State Key Laboratory of Radiation Medicine and ProtectionSoochow UniversitySuzhou215123PR China College of Pharmaceutical Sciences Soochow UniversitySuzhou215123PR China Jiangsu Institute of Hematology The First Affiliated Hospital of Soochow UniversityInstitute of Blood and Marrow Transplantation of Soochow UniversityCollaborative Innovation Center of HematologySoochow UniversitySuzhou215123PR China Orthopedic Institute Soochow UniversitySuzhou215007PR China

acute myeloid leukemia(AML)remains a most lethal hematological malignancy,partly because of its slow development of targeted therapies compared with other ***1 inhibitor,volasertib(Vol),is among the few molecular targeted drugs granted breakthrough therapy status for AML;however,its fast clearance and dose-limiting toxicity greatly restrain its clinical ***,we report that transferrin-guided polymersomes(TPs)markedly augment the targetability,potency and safety of Vol to ***-loaded TPs(TPVol)with 4%trans-ferrin exhibited best cellular uptake,effective down-regulation of p-PLK1,p-PTEN and p-AKT and superior apoptotic activity to free Vol in MV-4-11 leukemic *** injection of TPVol gave 6-fold higher AUC than free Vol and notable accumulation in AML-residing bone *** efficacy studies in orthotopic MV-4-11 leukemic model demonstrated that TPVol significantly reduced leukemic cell proportions in periphery blood,bone marrow,liver and spleen,effectively enhanced mouse survival rate,and impeded bone *** transferrin-guided nano-delivery of molecular targeted drugs appears to be an interesting strategy towards the development of novel treatments for AML.

关键词： Targeted delivery acute myeloid leukemia Polo-like kinase 1 Molecular targeted drug

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Risk factors for chronic graft-versus-host disease after anti-thymocyte globulin-based haploidentical hematopoietic stem cell transplantation in acute myeloid leukemia

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Frontiers of Medicine 2019年第6期13卷 667-679页

作者： Meng Lv Xiaohui Zhang Lanping Xu Yu Wang Chenhua Yan Huan Chen Yuhong Chen Wei Han Fengrong Wang Jingzhi Wang Kaiyan Liu Xiaojun Huang Xiaodong Mo Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing 100044China Peking-Tsinghua Center for Life Sciences Academy for Advanced Interdisciplinary StudiesPeking UniversityBeijing 100044China

Chronic graft-versus-host disease(cGVHD)is a major complication following unmanipulated haploidentical hematopoietic stem cell transplantation(haplo-HSCT).We aimed to identify the risk factors for cGVHD in patients who underwent anti-thymocyte globulin-based haplo-HSCT for acute myeloid leukemia(n=280).The diagnosis of cGVHD was in accordance with the National Institutes of Health consensus criteria.A total of 169 patients suffered from *** patients who had 3 loci mismatched had a higher 8-year incidence of cGVHD(total,66.0%vs.53.7%,P=0.031;moderate to severe,42.4%vs.30.1%,P=0.036)than the patients who had 1 to 2 loci *** patients who had maternal donors had a higher 8-year incidence of moderate to severe cGVHD(49.2%vs.32.9%,P=0.024)compared with the patients who had other *** patients who had grades III to IV acute GVHD(aGVHD)had higher 8-year incidence of cGVHD(total,88.0%vs.50.4%,P<0.001;moderate to severe,68.0%vs.27.0%,P<0.001)compared with the patients without *** multivariate analysis,grades III to IV aGVHD was the only independent risk factor for ***,further interventions should be considered in patients with severe aGVHD to prevent cGVHD.

关键词： acute graft-versus-host disease chronic graft-versus-host disease National Institutes of Health consensus criteria acute myeloid leukemia anti-thymocyte globulin

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Differential signaling of Flt3 activating mutations in acute myeloid leukemia:a working model

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Protein & Cell 2011年第2期2卷 108-115页

作者： Perry M.Chan Neuroscience Research Partnership Biomedical Sciences Instituteaffiliated with Institute of Molecular and Cell BiologyASTARSingapore 138673Singapore

Receptor tyrosine kinases couple a wide variety of extracellular cues to cellular *** class III subfamily comprises the platelet-derived growth factor receptor,c-Kit,Flt3 and c-Fms,all of which relay cell proliferation signals upon ligand ***,mutations in these proteins that confer ligand-independent activation are found in a subset of *** mutations cluster in the juxtamembrane(JM)and catalytic tyrosine kinase domain(TKD)*** the case of acute myeloid leukemia(AML),the juxtamembrane(named ITD for internal tandem duplication)and TKD Flt3 mutants differ in their spectra of clinical *** the mechanism of aberrant activation has been largely elucidated by biochemical and structural analyses of mutant kinases,the differences in disease presentation cannot be attributed to a change in substrate specificity or signaling strength of the catalytic *** review discusses the latest literature and presents a working model of differential Flt3 signaling based on mis-localized juxtamembrane autophosphorylation,to account for the disease *** will have bearing on therapeutic approaches in a complex disease such as AML,for which no efficacious drug yet exists.

关键词： acute myeloid leukemia receptor tyrosine kinase oncogenic mutation autoinhibition intracellular traf-ficking

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NK cells play a significant role in immunosurveillance at the early stage of MLL-AF9 acute myeloid leukemia via CD226/CD155 interactions

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Science China(Life Sciences) 2015年第12期58卷 1288-1298页

作者： WANG YaJie CHEN Chen DONG Fang MA ShiHui XU Jing GONG YueMin CHENG Hui ZHOU Yuan CHENG Tao HAO Sha State Key Laboratory of Experimental Hematology Institute of Hematology& Blood Diseases Hospital Collaborative Innovation Center for Cancer Medicine Center for Stem Cell Medicine Chinese Academy of Medical Sciences & Peking Union Medical College Department of Stem Cell and Regenerative Medicine Chinese Academy of Medical Sciences & Peking Union Medical College

acute myeloid leukemia(AML) is an aggressive hematological malignancy, and the mechanism underlying immune system involvement in leukemia development is unclear. In the present study, we utilized a myeloid/lymphoid or mixed-lineage leukemia; translocated to, 3(MLLT3/MLL-AF9)-induced AML mouse model with or without exposure to irradiation. We found that the leukemia cells could survive and expand in hosts with intact immune systems, whereas leukemia progression was accelerated in mice with impaired immune systems. Moreover, the leukemia cells escaped from host immunosurveillance via editing their immunogenicity, including the up-regulation of an inhibitory antigen(i.e., CD47) and the down-regulation of active antigens(i.e., CD86, CD54, retinoic acid early transcript(RAE), histocompatibility 2, D region locus b(H2-Db) and H2-Dd). Natural killer(NK) cells were activated in the early phase of AML progression, whereas T cells were stimulated in the late phase. Furthermore, NK cell depletion showed that NK cells were necessary for the elimination of leukemia cells in our AML mouse model. Notably, CD155/CD226 primarily mediated the interaction between NK cells and leukemia cells and contributed to the antitumor effects of NK cells during the early phase of AML. Clinical data from patients with diverse hematological malignancies showed that CD155 expression was decreased in hematological malignancies. Taken together, our results demonstrate that NK cells play a pivotal role in immunosurveillance against leukemia cells during the early stage of AML primarily through the CD226/CD155 interaction; however, NK cells are not sufficient to eliminate leukemia cells.

关键词： acute myeloid leukemia natural killer cell immunosurveillance

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Re-induction with modified CLAG regimen in relapsed or refractory acute myeloid leukemia in children bridging to allogeneic hematopoietic stem cell transplantation

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World Journal of Pediatrics 2020年第2期16卷 152-158页

作者： Na Zhang Jing-Bo Shao Hong Li Jing-Wei Yang Kai Chen Jia-Shi Zhu Hui Jiang Department of Hematology and Oncology Shanghai Children's HospitalShanghai Jiao Tong UniversityNo.24lane 1400West Beijing RoadShanghai 200040China

Background The prognosis for relapsed or refractory acute myeloid leukemia(RR-AML)in children is poor,and the preferred salvage chemotherapy is *** regimen is cladribine,cytarabine,and granulocyte-colony stimulating factor(CLAG),but little is known about its efficacy and safety in children with *** We enrolled RR-AML patients aged 0-18 years who received modified CLAG regimen for re-induction between July 1,2015 and April 1,2018,or conventional induction between August 1,2011 and April 1,*** were followed up to March 31,*** underwent allogeneic stem cell transplantation(allo-SCT)or chemotherapy after the induction of complete remission(CR).The CR rate,survival,and side effects were *** The CR rate for induction was 66.7%after one cycle and 75.0%after two cycles of the CLAG regimen in 12 *** nine children who received conventional chemotherapy had a CR rate of 22.2%after one cycle and 33.3%after two cycles(P=0.087 ***).The 3-year event-free survival(EFS)of the CLAG group and the conventional treatment group were 44.4±15.7%and 22.2±13.8%(P=0.112).The 3-year overall survival of the two groups were 59.5±16.2%and 22.2%±13.8%(P=0.057).The 3-year EFS for allo-SCT and chemotherapy after CLAG regimen was 66.7±19.2%and 25.0±21.7%(P=0.015).A single case of chemotherapy-related death was *** Our data suggest a promising CR rate using CLAG salvage treatment in childhood ***-SCT after CR may improve the long-term outcome in these patients.

关键词： acute myeloid leukemia Children Cladribine Refractory Relapsed

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Berberine targets the electron transport chain complex I and reveals the landscape of OXPHOS dependency in acute myeloid leukemia with IDH1 mutation

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Chinese Journal of Natural Medicines 2023年第2期21卷 136-145页

作者： HUANG Zhe SHEN Yunfu LIU Wenjun YANG Yan GUO Ling YAN Qin WEI Chengming GUO Qulian FAN Xianming MA Wenzhe State Key Laboratory of Quality Research in Chinese Medicine Macao University of Science and TechnologyMacao 999078China Department of Pediatrics the Affiliated Hospital of Southwest Medical UniversitySichuan Clinical Research Center for Birth DefectsLuzhou 646000China Department of Respiratory and Critical Care Medicine the Affiliated Hospital of Southwest Medical UniversityLuzhou 646000China

Metabolic reprogramming,a newly recognized trait of tumor biology,is an intensively studied prospect for oncology *** numerous tumors and cancer cell subpopulations,oxidative phosphorylation(OXPHOS)is essential for their biosynthetic and bioenergetic *** cells with mutations in isocitrate dehydrogenase 1(IDH1)exhibit differentiation arrest,epigenetic and transcriptional reprogramming,and sensitivity to mitochondrial OXPHOS *** this study,we report that berberine,which is widely used in China to treat intestinal infections,acted solely at the mitochondrial electron transport chain(ETC)complex I,and that its association with IDH1 mutant inhibitor(IDH1^(m)i)AG-120 decreased mitochondrial activity and enhanced antileukemic effect in vitro and in *** study gives a scientific rationale for the therapy of IDH1 mutant acute myeloid leukemia(AML)patients using combinatory mitochondrial targeted medicines,particularly those who are resistant to or relapsing from IDH1m i.

关键词： Berberine Oxidative phosphorylation Complex I Mutant IDH1 acute myeloid leukemia

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Red blood cell membrane-coated FLT3 inhibitor nanoparticles to enhance FLT3-ITD acute myeloid leukemia treatment

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Chinese Chemical Letters 2024年第9期35卷 303-308页

作者： Jisheng Liu Junli Chen Xifeng Zhang Yin Wu Xin Qi Jie Wang Xiang Gao Department of Neurosurgery and Institute of Neurosurgery State Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan UniversityChengdu 610041China West China School of Basic Medical Sciences&Forensic Medicine Sichuan UniversityChengdu 610041China Department of Hematology West China HospitalSichuan UniversityChengdu 610041China

FMS-like tyrosine kinase 3(FLT3)is a viable and important therapeutic target for acute myeloid leukemia(AML).FLT3 internal tandem duplication(FLT3-ITD)mutations have been identified in approximately 30%of AML patients,and are associated with unfavorable prognosis,higher risk of relapse,drug resistance,and poor clinical *** FLT3 inhibitors have demonstrated promising efficacy,they cannot cure AML or even significantly extend the lives of patients with FLT3-ITD *** is partly because of poor water solubility,insufficient membrane penetration and short half-life of small molecule ***,the presence of enzymes like CYP3A4 in bone marrow accelerate the elimination and metabolism of FLT3 inhibitors,resulting in low plasma concentrations and side *** we report the erythrocyte membrane-camouflaged FLT3 inhibitor nanoparticles to enhance FLT3-ITD AML ***,we physically coextruded red blood cell(RBC)membrane vesicles with nanoparticles derived from FLT3 inhibitor F30 to obtain F30@RBC-M,which exhibited comparable potent FLT3-ITD inhibitory effects compared to free F30 in vitro,while displaying a higher potent antitumor efficacy in xenograft models due to the prolonged circulation ***,administration of F30@RBC-M significantly extended the survival of mice in a transplanted mouse model than F30 free *** findings suggest that RBC membrane-coated nanoparticles derived from FLT3 inhibitors hold promise as a tool to enhance the therapeutic efficacy to treat FLT3-ITD AML.

关键词： FLT3-ITD acute myeloid leukemia AML Red blood cell membrane Biomimetics

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