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Effect of Compound Zhebei Granule(复方浙贝颗粒)Combined with Chemotherapy on Surface Markers of leukemia Stem Cell in Patients with acute myeloid leukemia

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Chinese Journal of Integrative Medicine 2016年第6期22卷 438-444页

作者：王婧赖宗浪陈信义李冬云张雅月马薇褚雨霆石凤芹杨璐侯丽 Department of Oncology and Hematology Dongzhimen Hospital Affiliated to Beijing University of Chinese Medicine Department of Oncology Chongqing Hospital of Traditional Chinese Medicine

Objective： To observe the effects of Compound Zhebei Granule （复方浙贝颗粒, CZBG） combined with chemotherapy on surface markers of leukemia stem cell （LSC） in the bone marrow of patients with acute myeloid leukemia （AML）. Methods： Seventy-eight patients with AML received bone marrow aspiration and the percentages of CD34＋CD123＋ and CD33＋CD123＋ cells were tested using flow cytometry method. A total of 24 refractory or relapsed AML patients were enrolled and treated with one cycle of standard chemotherapy combined with CZBG. Bone marrow samples were obtained before and after treatment, and the percentages of CD34＋CD123~ and CD33＋CD123＋ cells were examined by flow cytometry. Results： Compared with refractory or relapsed AML patients, patients achieved remission had a significant lower percentage of CD34＋CD123＋ cells （P〈0.01） and CD33＋CD123＋ cells （P〈0.01）, indicating that controlling the LSC percentage may be important for patients with AML to achieve sustainable remission. Compared with those before treatment, the expression levels of CD34＋CD123＋ were significantly decreased after CZBG combined with chemotherapy treatment （P〈0.01）. The percentages of CD34＋CD123＋ cells and CD33＋CD123＋ in patients achieving complete remission after CZBG combined with chemotherapy treatment were both significantly lower than those in patients with non- remission （P〈0.01）. Conclusion： CZBG combining chemotherapy could reduce the percentages of CD34＋CD123＋ and CD33＋CD123＋ LSC, which might improve the clinical efficacy of refractory or relapsed AML.

关键词： acute myeloid leukemia Compound Zhebei Granule clinical study leukemia stem cell

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Molecular landscape in acute myeloid leukemia: where do we stand in 2016

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Cancer Biology & Medicine 2016年第4期13卷 474-482页

作者： Karam Al-Issa Aziz Nazha leukemia Program Department of Hematology and Oncology Cleveland Clinic Taussig Cancer Institute

acute myeloid leukemia(AML) is a clonal disorder characterized by the accumulation of complex genomic alterations that define the disease pathophysiology and overall outcome. Recent advances in sequencing technologies have described the molecular landscape of AML and identified several somatic alterations that impact overall survival. Despite all these advancement, several challenges remain in translating this information into effective therapy. Herein we will review the molecular landscape of AML and discuss the impact of the most common somatic mutations on disease biology and outcome.

关键词： acute myeloid leukemia molecular landscape somatic mutations

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Different Outcome of myeloid Sarcoma with Spinal Cord Compression Preceding acute myeloid leukemia:Report of Two Cases and Review of Literatures

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Chinese Journal of Cancer Research 2010年第2期22卷 156-162页

作者： Qiang Yin Yang-yang Zhou Duo Chen Wen-liang Li Key Laboratory of Cancer Prevention and Therapy Department of Neurosurgery and Neuro-oncology Tianjin Medical University Cancer Hospital Tianjin 300060 China Department of Neurosurgery Shengjing Hospital Affiliated to China Medical University Shenyang China

myeloid sarcomas （MS） preceding acute myeloid leukemia （AML） are rare, which presenting as acute spinal cord compression is even rare. Here we report two new cases of myeloid sarcoma patients, whose outcomes were different. Twenty-seven patients with spinal MS preceding AML have been reported to date, including the two cases presented in this article. Surgical decompression was performed in 25 of the 27 patients, and 23 of these received additional anti-AML therapy. Considering our patients and the published cases in the literature we suggest that immunohistochemical study plays an essential role in arriving at a correct diagnosis of MS, and that emergency surgery to resect spinal MS is an available treatment to make neural function recovery, and that the disease must be treated with intensive chemotherapy similar to that used to treat AML as soon as possible after resection or irradiation of the tumor.

关键词： Spine myeloid sarcoma Immunhistochemistry acute myeloid leukemia

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Bone marrow niche-mediated survival of leukemia stem cells in acute myeloid leukemia: Yin and Yang

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Cancer Biology & Medicine 2016年第2期13卷 248-259页

作者： Hong-Sheng Zhou Bing Z.Carter Michael Andreeff Section of Molecular Hematology and Therapy Department of Leukemia The University of Texas M.D.Anderson Cancer Center Department of Hematology Nanfang Hospital Southern Medical University

acute myeloid leukemia （AML） is characterized by the accumulation of circulating immature blasts that exhibit uncontrolled growth, lack the ability to undergo normal differentiation, and have decreased sensitivity to apoptosis. Accumulating evidence shows the bone marrow （BM） niche is critical to the maintenance and retention of hematopoietic stem cells （HSC）, including leukemia stem cells （LSC）, and an increasing number of studies have demonstrated that crosstalk between LSC and the stromal cells associated with this niche greatly influences leukemia initiation, progression, and response to therapy. Undeniably, stromal cells in the BM niche provide a sanctuary in which LSC can acquire a drug-resistant phenotype and thereby evade chemotherapy- induced death. Yin and Yang, the ancient Chinese philosophical concept, vividly portrays the intricate and dynamic interactions between LSC and the BM niche. In fact, LSC-induced microenvironmental reprogramming contributes significantly to leukemogenesis. Thus, identifying the critical signaling pathways involved in these interactions will contribute to target optimization and combinatorial drug treatment strategies to overcome acquired drug resistance and prevent relapse following therapy. In this review, we describe some of the critical signaling pathways mediating BM niche-LSC interaction, including SDFI/CXCL12, Wnt/β-catenin, VCAM/VLA-4/NF-κB, CD44, and hypoxia as a newly-recognized physical determinant of resistance, and outline therapeutic strategies for overcoming these resistance factors.

关键词： Bone marrow niche leukemia stem cell acute myeloid leukemia Yin and Yang

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Association of polymorphisms of cytosine arabinoside- metabolizing enzyme gene with therapeutic efficacy for acute myeloid leukemia

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Chinese Medical Journal 2012年第12期125卷 2137-2143页

作者： XU Pei-pei CHEN Bao-an FENG Ji-feng CHENG Lu XIA Guo-hua LI Yu-feng QIAN Jun DING Jia-hua LU Zu-hong WANG Xue-mei XU Ke Margaret Schultz Department of Hematology Zhongda Hospital and Faculty ofOncology Medical School Southeast University Nanjing Jiangsu210009 China Department of Oncology Jiangsu Province Cancer InstituteNanjing Jiangsu 210009 China State Key Laboratory for Bioelectronics Southeast UniversityNanjing Jiangsu 210096 China Department of Hematology Huaian First People＇s HospitalHuaian Jiangsu 223300 China Department of Hematology Zhenjiang First People＇s HospitalZhenjiang Jiangsu 212002 China Sloan Kettering Cancer Center New York 10065 USA Weill Comell Medical College New York 10065 USA

Background The cytosine arabinoside （Ara-C）-based chemotherapy is the major remedial measure for acute myeloid leukemia （AML）. Deoxycytidine kinase （DCK） and cytidine deaminase （CDA） are the key enzymes in the metabolism of Ara-C. Many single nucleotide polymorphisms （SNPs） and haplotypes of DCK and CDA, which contribute to susceptibility to Ara-C, have been identified in Africans and Europeans. However, there has been no report about the relation among three SNPs in DCK （rs115543896, rs72552079, and rs111454937） and two SNPs in CDA （rs2072671 and rs60369023）, and their clinical response to Ara-C for a Chinese population. In this study, we aimed to investigate whether these five SNPs are associated with the therapeutic outcomes of Ara-C-based chemotherapy regimens in patients with AML. Methods A total of 151 Chinese patients with AML were enrolled in our study. SNPs genotyping were performed using the MassARRAY system by means of the matrix-assisted laser desorption ionization-time of flight mass spectrometry （MALDI-TOF-MS） method. Results The results illustrated that DCKrs111454937 AA genotype was more frequent in patients with higher platelet count, and A allele frequency was significantly higher in the group 〈40 years, lower white blood cell （WBC） count patients group and the group with platelet counts 〉60xl0e/L. Meanwhile, both DCKrs72552079 TC （OR=1.225, 95% C1=1.225-9.851, P=0.0192） and CDArs60369023 GA （OR=9.851,95% C1=1.31-77.93, ,~=-0.0263） significantly improved Ara-C-based chemotherapy response. While DCKrs11554389 AA （OR=0.147, 95% CI=0.027-0.801, P=0.0267） was associated with the decrease of Ara-C-based chemotherapy response. Conclusion It is evident that the DCK and CDA polymorphisms might be the important markers for the AML patients＇ therapy outcomes in a Chinese population.

关键词： deoxycytidine kinase cytidine deaminase single nucleotide polymorphisms acute myeloid leukemia

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Treatment strategies in acute myeloid leukemia

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Chinese Medical Journal 2011年第9期000卷 1409-1421页

作者： HAN Li-na ZHOU Jin Jan Jacob Schuringa Edo Vellenga Department of Hematology University Medical Center Groningen University of Groningen Groningen Netherlands Department of Hematology the First Clinical College of Harbin Medical University Harbin Heilongjiang 150001 China

Objective To summarize the risk stratification and current treatment strategies for acute myeloid leukemia （AML） and discuss the role of emerging novel agents that might be applied in future clinical *** sources The data in this article were collected from PubMed database with relevant English articles published from 1991 to *** selection Articles regarding the risk stratification and therapeutic options of AML, as well as the characteristics of leukemic stem cells were *** AML is a heterogeneous disease with variable clinical outcome dependent on several prognostic factors,including age, cytogenetics and molecular markers. The advances in the understanding of AML pathogenesis and development will generate potential novel agents that might improve the treatment results of standard *** Deeper insight into the multiple transforming events of AML may aid us in designing combinations of small molecule inhibitors based on the individual patient characteristics.

关键词： acute myeloid leukemia leukemic stem cell treatment novel agents

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Efficacy and Safety of Unmanipulated Haploidentical Related Donor AIIogeneic Peripheral Blood Stem Cell Transplantation in Patients with Relapsed/Refractory acute myeloid leukemia

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Chinese Medical Journal 2018年第7期131卷 790-798页

作者： Li-Ping Dou Hong-Hua Li Lu Wang Fei Li Wen-Rong Huang Li Yu Dai-Hong Liu Department of Hematology Chinese PLA General Hospital Medical School of Chinese PLA Beijing 100853 China

Background： Studies of haploidentical-related donor （HRD） stem cell transplantation using a combination of peripheral blood stem cells （PBSCs） and bone marrow as the graft have reported encouraging results for patients with hematological diseases. However, few studies specifically reported transplantation of only PBSCs from HRDs among patients with relapsed or refractory acute myeloid leukemia （AML）. Here, the long-term outcomes and side effects of unmanipulated HRD PBSC transplantation （HRD-PBSCT） for relapsed/refractory AML were analyzed. Methods： We performed a retrospective analysis of the outcomes in relapsed/refractory AML patients who underwent PBSCT from HRDs （n = 36）. Results： Thirty-one （86.1%） patients in the HRD-PBSCT group achieved platelet recovery. The cumulative incidence of acute graft-versus-host disease （aGVHD） in the HRD-PBSCT group was 40.00%, and the cumulative incidence of grades 2-4 aGVHD in this group was 13.33%. A total of 13 patients in the HRD-PBSCT group had recurrent disease at a median of 183 days after transplantation （range： 10-1700 days）, reaching cumulative incidences of relapse of 50.28% at 5 years. On multivariate analysis, donor age and patient age 〉40 years were independent risk factors for inferior disease-free survival or overall survival （P 〈 0.05）. The results of the present study demonstrate rapid and complete neutrophil engraftment, a low incidence of grade 2-4 aGVHD, and promising survival rates in patients after HRD-PBSCT. Thus, granulocyte colony-stimulating factor-primed PBSCs may be a reliable graft source in unmanipulated HRD-HSCT under myeloablative conditioning when no matched sibling donor is available. Conclusions： Our results support the feasibility, effectiveness, and tolerability of PBSCs as a graft source in unmanipulated HRD transplantation under myeloablative conditioning in patients with leukemia.

关键词： acute myeloid leukemia Haploidentical Transplantation Peripheral Blood Stem Cell Transplantation Recurrence

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B7-H3 in acute myeloid leukemia:From prognostic biomarker to immunotherapeutic target

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Chinese Medical Journal 2024年第21期137卷 2540-2551页

作者： Xiao Tan Xiangyu Zhao Peking University People’s Hospital Peking University Institute of HematologyNational Clinical Research Center for Hematologic DiseaseBeijing Key Laboratory of Hematopoietic Stem Cell TransplantationBeijing 100044China

B7-H3(CD276),an immune checkpoint protein of the B7 family,exhibits significant upregulation in solid tumors and hematologic malignancies,exerting a crucial role in their *** distinct differential expression of B7-H3 between tumors and normal tissues and its multifaceted involvement in tumor pathogenesis position it as a promising therapeutic target for *** the context of acute myeloid leukemia(AML),B7-H3 is prominently overexpressed and closely associated with unfavorable prognoses,yet it has remained *** various ongoing clinical trials demonstrating the potential efficacy of immunotherapies targeting B7-H3,the precise underlying mechanisms responsible for B7-H3-mediated proliferation and immune evasion in AML remain *** view of this,we comprehensively outline the current research progress concerning B7-H3 in AML,encompassing in-depth discussions on its structural attributes,receptor interactions,expression profiles,and biological significance in normal tissues and ***,we delve into the protumor effects of B7-H3 in AML,examine the intricate mechanisms that underlie its function,and discuss the emerging application of B7-H3-targeted therapy in AML *** juxtaposing B7-H3 with other molecules within the B7 family,this review emphasizes the distinctive advantages of B7-H3,not only as a valuable prognostic biomarker but also as a highly promising immunotherapeutic target in AML.

关键词： B7-H3(CD276) B7 family acute myeloid leukemia Immune checkpoint Immunotherapy

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MicroRNAs of bone marrow mesenchymal stem cell-derived exosomes regulate acute myeloid leukemia cell proliferation and apoptosis

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Chinese Medical Journal 2020年第23期133卷 2829-2839页

作者： Yi-Chuan Xu Yan-Si Lin Ling Zhang Ying Lu Yan-Ling Sun Zhi-Gang Fang Zi-Yu Li Rui-Fang Fan Department of Hematology The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China Department of General Practice Sun Yat-Sen Memorial HospitalSun Yat-Sen UniversityGuangzhouGuangdong 510120China Department of Surgical Intensive Care Unit The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China Department of Prevention and Health The Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouGuangdong 510630China

Background:acute myeloid leukemia(AML)is a malignant hematological disease,originating from hematopoiesis stem cell differentiation obstruction and clonal *** reagents or biologicals for the treatment of AML are urgently needed,and exosomes have been identified as candidate biomarkers for disease diagnosis and *** study aimed to investigate the effects of exosomes from bone marrow mesenchymal stem cells(BMSCs)on AML cells as well as the underlying microRNA(miRNA)-mediated ***:Exosomes were isolated using a precipitation method,followed by validation using marker protein expression and nanoparticle tracking *** expressed miRNAs were identified by deep RNA sequencing and confirmed by quantitative real-time polymerase chain reaction(qPCR).Cell proliferation was assessed by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt method,and cell cycle progression and apoptosis were detected by flow *** gene expression was analyzed by qPCR and Western blotting(WB).Significant differences were determined using Student’s t test or analysis of ***:BMSCs-derived exosomes effectively suppressed cell proliferation(both P<0.0001 at 10 and 20μg/mL)and cell cycle progression(P<0.01 at G0-G1 stage),and also significantly enhanced cell apoptosis(P<0.001)in KG-1a *** were 1167 differentially expressed miRNAs obtained from BMSCs-derived exosomes compared with KG-1a cell-derived exosomes(P<0.05).Knockdown of hsa-miR-124-5p in BMSCs abrogated the effects of BMSCs-derived exosomes in regulating KG-1a such as the change in cell proliferation(both P<0.0001 *** KG-1a cell[NC]at 48 and 72 h).KG-1a cells treated with BMSCs-derived exosomes suppressed expression of structural maintenance of chromosomes 4(P<0.001 *** by qPCR and P<0.0001 *** by WB),which is associated with the progression of various *** BMSCs-derived exosomes effect

关键词： Exosomes Mesenchymal stem cell acute myeloid leukemia hsa-miR-124-5p

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Internal m^(6)A and m^(7)G RNA modifications in hematopoietic system and acute myeloid leukemia

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Chinese Medical Journal 2024年第9期137卷 1033-1043页

作者： Xiaoxu Zhang Yanni Ma Jia Yu Rui Su Xiaoshuang Wang State Key Laboratory of Common Mechanism Research for Major Diseases State Key Laboratory for ComplexSevereand Rare DiseasesInstitute of Basic Medical SciencesChinese Academy of Medical Sciences/Peking Union Medical CollegeBeijing 100005China Department of Systems Biology Beckman Research Institute of City of HopeMonroviaCA 91016USA The Institute of Blood Transfusion Chinese Academy of Medical Sciences/Peking Union Medical CollegeChengduSichuan 610052China Key Laboratory of RNA and Hematopoietic Regulation Chinese Academy of Medical SciencesBeijing 100005China Department of Biochemistry and Molecular Biology Chinese Academy of Medical SciencesSchool of Basic Medicine Peking Union Medical CollegeBeijing 100005China

Epitranscriptomics focuses on the RNA-modification-mediated post-transcriptional regulation of gene *** past decade has witnessed tremendous progress in our understanding of the landscapes and biological functions of RNA modifications,as prompted by the emergence of potent analytical *** hematopoietic system provides a lifelong supply of blood cells,and gene expression is tightly controlled during the differentiation of hematopoietic stem cells(HSCs).The dysregulation of gene expression during hematopoiesis may lead to severe disorders,including acute myeloid leukemia(AML).Emerging evidence supports the involvement of the mRNA modification system in normal hematopoiesis and AML pathogenesis,which has led to the development of small-molecule inhibitors that target N6-methyladenosine(m^(6)A)modification machinery as ***,we summarize the latest findings and our most up-to-date information on the roles of m^(6)A and N7-methylguanine in both physiological and pathological conditions in the hematopoietic ***,we will discuss the therapeutic potential and limitations of cancer treatments targeting m^(6)A.

关键词： N6-methyladenosine N7-methylguanine Hematopoiesis acute myeloid leukemia Therapeutic target RNA modifications

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