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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

The modulation of radiation-induced cell death by genistein in K562 cells:Activation of thymidine kinase 1

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Cell Research 2004年第4期14卷 295-302页

作者： Min Ho JEONG,Young Hee JIN,Eun Young KANG,Wol Soon JO,Hwan Tae PARK,Jae Dong LEE,Yeo Jin YOO,Soo Jin JEONG Research Supporting Center for Medical Science (BK21 program) Dong-A University College of Medicine Busan Korea Research Supporting Center for Medical Science (BK21 program) Dong-A University College of Medicine Busan Korea Research Supporting Center for Medical Science (BK21 program) Dong-A University College of Medicine Busan Korea Research Supporting Center for Medical Science (BK21 program) Dong-A University College of Medicine Busan Korea Research Supporting Center for Medical Science (BK21 program) Dong-A University College of Medicine Busan Korea Department of Microbiology Pusan National University Busan Korea Research Supporting Center for Medical Science (BK21 program) Dong-A University College of Medicine Busan Korea Research Supporting Center for Medical Science (BK21 program) Dong-A University College of Medicine Busan Korea Virus Tumor Biology Section Laboratory of Cellular Oncology Center for Cancer Research National Cancer Institutes National Institute of Health Bethesda MD 20892 USA

Ionizing radiation is one of the most effective tools in cancer therapy. In a previous study, we reported that protein tyrosine kinase (PTK) inhibitors modulate the radiation responses in the human chronic myelogenous leukemia (CML) cell line K562. The receptor tyrosine kinase inhibitor, genistein, delayed radiation-induced cell death, while non-recepter tyrosine kinase inhibitor, herbimycin A (HMA) enhances radiation-induced apoptosis. In this study, we focused on the modulation of radiation-induced cell death by genistein and performed PCR-select suppression subtractive hybridization (SSH) to understand its molecular mechanism. We identified human thymidine kinase 1 (TK1), which is cell cycle regulatory gene and confirmed expression of TK1 mRNA by Northern blot analysis. Expression of TKl mRNA and TK1 enzymatic activity were parallel in their increase and decrease. TK1 is involved in G1-S phase transition of cell cycle progression. In cell cycle analysis, we showed that radiation induced G2 arrest in K

关键词： K562 radiation cell death genistein thymidine kinase 1 cell cycle.

Wilms’tumor gene(WT1)is strongly expressed in high-risk subsets of pediatric acute lymphoblastic leukemia

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Cancer Drug Resistance 2018年第4期1卷 250-265页

作者： Fatih M.Uckun Sanjive Qazi Biomarker Research program AresMIT Biomedical Computational Strategies(ABCS)MinneapolisMinnesota 55110USA Biotherapy program Ares PharmaceuticalsLLCSt.PaulMinnesota 55110USA Bioinformatics program Gustavus Adolphus CollegeSt.PeterMinnesota 56082USA

Aim:The purpose of the present study was to perform a comprehensive analysis of WT1 gene expression in high-risk pediatric acute lymphoblastic leukemia(ALL).Methods:We performed a meta-analysis of WT1 gene expression for normal hematopoietic cells *** leukemia cells from 801 pediatric ALL samples deposited in the Oncomine database combined with an in-depth gene expression analysis using our in-house database of gene expression profiles of primary leukemia cells from 1416 pediatric ALL *** also examined the expression of WT1 in primary leukemic cells from 299 T-lineage ALL patients in the Oncomine database and 189 T-lineage ALL patients in the archived datasets GSE13159,GSE13351,and ***:Our data provide unprecedented evidence that primary leukemia cells from patients with MLL gene rearrangements(MLL-R)express highest levels of WT1 expression within the high-risk subsets of pediatric B-lineage ***,MLL-R^(+)patients exhibited>6-fold higher expression levels of the WT1 gene compared to the other B-lineage ALL subtypes combined(Pleukemia cells than in normal hematopoietic cells and revealed that WT1 expression level was substantially higher in steroid-resistant infant leukemia cells when compared to non-leukemic healthy bone marrow ***,our study demonstrates for the first time that the WT1-regulated EWSR1,TP53,U2AF2,and WTAP genes(i.e.,WT1 interactome)were differentially upregulated in MLL-R^(+)leukemia cells illustrating that the MLL-regulatory pathway is aberrantly upregulated in MLL-R^(+)pediatric B-lineage *** novel insights provide a compelling rationale for targeting WT1 in second line treatment of MLL-R^(+)pediatric B-lineage ALL,including MLL-R^(+)infant ***,our study is the first to demonstrate that leukemia cells from 370 Ph-like patients had

关键词： Wilms’tumor gene WT1 gene leukemia chemotherapy resistance immunotherapy

Ex vivo expansion of hematopoietic stem cells

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Science China(Life Sciences) 2015年第9期58卷 839-853页

作者： XIE JingJing ZHANG ChengCheng Taishan Scholar Immunology program Binzhou Medical University Departments of Physiology and Developmental Biology University of Texas Southwestern Medical Center

Ex vivo expansion of hematopoietic stem cells(HSCs) would benefit clinical applications in several aspects, to improve patient survival, utilize cord blood stem cells for adult applications, and selectively propagate stem cell populations after genetic manipulation. In this review we summarize and discuss recent advances in the culture systems of mouse and human HSCs, which include stroma/HSC co-culture, continuous perfusion and fed-batch cultures, and those supplemented with extrinsic ligands, membrane transportable transcription factors, complement components, protein modification enzymes, metabolites, or small molecule chemicals. Some of the expansion systems have been tested in clinical trials. The optimal condition for ex vivo expansion of the primitive and functional human HSCs is still under development. An improved understanding of the mechanisms for HSC cell fate determination and the HSC culture characteristics will guide development of new strategies to overcome difficulties. In the future, development of a combination treatment regimen with agents that enhance self-renewal, block differentiation, and improve homing will be critical. Methods to enhance yields and lower cost during collection and processing should be employed. The employment of an efficient system for ex vivo expansion of HSCs will facilitate the further development of novel strategies for cell and gene therapies including genome editing.

关键词： ex vivo expansion hematopoietic stem cells niche signal transduction cord blood transplantation SCID-repopulating cell genome ed

Clinical management of myelodysplastic syndrome/myeloproliferative neoplasm overlap syndromes

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Cancer Biology & Medicine 2016年第3期13卷 360-372页

作者： Joseph A.Clara David A.Sallman Eric Padron Department of Internal Medicine University of South Florida Morsani College of Medicine Malignant Hematology program H.Lee Moffitt Cancer Center and Research Institute

The myelodysplastic/myeloproliferative neoplasms(MDS/MPNs) are a unique group of hematologic malignancies characterized by concomitant myelodysplastic and myeloproliferative features. According to the 2008 WHO classification, the category includes atypical chronic myeloid leukemia(a CML), chronic myelomonocytic leukemia(CMML), juvenile myelomonocytic leukemia(JMML), MDS/MPN-unclassifiable(MDS/MPN-U), and the provisional entity refractory anemia with ring sideroblasts and thrombocytosis(RARS-T). Although diagnosis currently remains based on clinicopathologic features, the incorporation of nextgeneration platforms has allowed for the recent molecular characterization of these diseases which has revealed unique and complex mutational profiles that support their distinct biology and is anticipated to soon play an integral role in diagnosis,prognostication, and treatment. Future goals of research should include the development of disease-modifying therapies, and further genetic understanding of the category will likely form the foundation of these efforts.

关键词： Myelodysplastic syndromes myeloproliferative neoplasms next-generation sequencing CMML aCML IMML MDS/MPN-U

Direct contact with bone marrow stromal cells promotes the invasions of SHI-1 leukemia cells

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Chinese Medical Journal 2013年第14期126卷 2731-2735页

作者： LI Zhen-jiang CHEN Zi-xing CEN Jian-nong HE Jun QIU Qiao-cheng Department of Hematology Second Affiliated Hospital of Nanchang University Nanchang Jiangxi 330006 China leukemia Research Unit Jiangsu Institute of Hematology First Affiliated Hospital of Soochow University Suzhou Jiangsu 215006 China

Background Interactions of tumor cells with the microenvironment were deemed to promote the tumor invasion and metastasis. CXC chemokine receptor 4 （CXCR4） and extracellular matrix metalloproteinase inducer （EMMPRIN） had reported to participate in this process. However the roles of bone marrow microenvironment in leukemic infiltration were not well investigated. Methods A co-culture system between SHI-1 cells and bone marrow stromal cells （BMSCs） is used to simulate the interactions of leukemic cells with their microenvironment. The trans-matrigel invasion was used to detect the capability of SHI-1 cells invasion. The BMSCs and SHI-1 cells were mixed in a ratio of 1：10 and added to the millicell chamber coated with matrigel. Either the co-culture supernatant or the functional blocking peptide of CXCR4 and EMMPRIN were added to the trans-matrigel invasion system. The expressions of EMMPRIN in SHI-1 cells and BMSCs were detected by RT-PCR. The changes of the expression of matrix metalloproteinase-2, 9 （MMP-2, MMP-9）, tissue inhibitor of metalloproteinase 2 （TIMP-2）, and CXCR4 mRNA in SHI-1 cells were determined by real-time PCR. The concentration of stromal cell derived factor 1 （SDF-1） in serum free supernatant was measured by ELISA. Results Both SHI-1 cells and BMSCs express EMMPRIN. SHI-1 cells could hardly invade the matrigel membrane; the co- culture supernatant did not induce the invasion of SHI-1 cells. When contacting directly with BMSCs, SHI-1 cells invaded to the lower chamber of millicell were significantly increased. The functional blocking peptide of CXCR4 and EMMPRIN could significantly inhibit the invasion triggered by BMSCs. When co-culturing with BMSCs, the expression of CXCR4, MMP-2, MMP-9 and TIMP-2 mRNA in SHI-1 cells were significantly elevated in company with a significantly higher level of SDF-1 in the co-cultured serum-free supernatant. Conclusion The interactions of leukemic cells and BMSCs play important roles in leukemic cell infiltration.

关键词： leukemia bone marrow stromal cells extramedullary infiltration EMMPRIN SDF-1/CXCR4

Optical coherence tomography and T cell gene expression analysis in patients with benign multiple sclerosis

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Neural Regeneration Research 2017年第8期12卷 1352-1356页

作者： John Soltys Qin Wang Yang Mao-Draayer University of Colorado Medical Scientist Training program(MSTP) AuroraCOUSA Department of Neurology University of Michigan Medical SchoolAnn ArborMIUSA

Benign multiple sclerosis is a retrospective diagnosis based primarily on a lack of motor symptom progression. Recent findings that suggest patients with benign multiple sclerosis experience non-motor symptoms highlight the need for a more prospective means to diagnose benign multiple sclerosis early in order to help direct patient care. In this study, we present optical coherence tomography and T cell neurotrophin gene analysis findings in a small number of patients with benign multiple sclerosis. Our results demonstrated that retinal nerve fiber layer was mildly thinned, and T cells had a distinct gene expression profile that included upregulation of interleukin 10 and leukemia inhibitory factor, downregulation of interleukin 6 and neurotensin high affinity receptor 1（a novel neurotrophin receptor）. These findings add evidence for further investigation into optical coherence tomography and m RNA profiling in larger cohorts as a potential means to diagnose benign multiple sclerosis in a more prospective manner.

关键词： neurotensin high affinity receptor 1 benign multiple sclerosis optical coherence tomography interleukin 10 T cell leukemia inhibitory factor optic neuritis neural regeneration

Emerging roles of NudC family： from molecular regulation to clinical implications

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Science China(Life Sciences) 2016年第5期59卷 455-462页

作者： Qiqin Fu Wei Wang Tianhua Zhou Yuehong Yang Department of Cell Biology and program in Molecular Cell Biology Zhejiang University School of Medicine Hangzhou 310058 China Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases Hanezhou 310003 China

Nuclear distribution gene C （NudC） was first found in Aspergillus nidulans as an upstream regulator of NudF, whose mamma- lian homolog is Lissencephaly 1 （Lisl）. NudC is conserved from fungi to mammals. Vertebrate NudC has three homologs： NudC, NudC-like protein （NudCL）, and NudC-like protein 2 （NudCL2）. All members of the NudC family share a conserved p23 domain, which possesses chaperone activity both in conjunction with and independently of heat shock protein 90 （Hsp90）. Our group and the others found that NudC homologs were involved in cell cycle regulation by stabilizing the components of the LIS l/dynein complex. Additionally, NudC plays important roles in cell migration, ciliogenesis, thrombopoiesis, and the in- flammatory response. It has been reported that NudCL is essential for the stability of the dynein intermediate chain and cilio- genesis via its interaction with the dynein 2 complex. Our data showed that NudCL2 regulates the LISl/dynein pathway by stabilizing LIS 1 with Hsp90 chaperone. The fourth distantly related member of the NudC family, CML66, a tumor-associated antigen in human leukemia, contains a p23 domain and appears to promote oncogenesis by regulating the IGF-1R-MAPK sig- naling pathway. In this review, we summarize our current knowledge of the NudC family and highlight its potential clinical relevance.

关键词： nuclear distribution gene C heat shock protein 90 p23 dynein Lissencephaly 1 cell cycle ciliogenesis

Targeting multiple signaling pathways:the new approach to acute myeloid leukemia therapy

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Signal Transduction and Targeted Therapy 2021年第1期6卷 41-69页

作者： Jenna LCarter Katie Hege Jay Yang Hasini AKalpage Yongwei Su Holly Edwards Maik Hüttemann Jeffrey WTaub Yubin Ge Cancer Biology Graduate program Wayne State University School of MedicineDetroitMIUSA MD/PhD program Wayne State University School of MedicineDetroitMIUSA Department of Oncology Wayne State University School of MedicineDetroitMIUSA Molecular Therapeutics program Barbara Ann Karmanos Cancer InstituteWayne State University School of MedicineDetroitMIUSA Center for Molecular Medicine and Genetics Wayne State University School of MedicineDetroitMIUSA National Engineering Laboratory for AIDS Vaccine Key Laboratory for Molecular Enzymology and EngineeringThe Ministry of EducationSchool of Life SciencesJilin UniversityChangchunChina Division of Pediatric Hematology/Oncology Children’s Hospital of MichiganDetroitMIUSA Department of Pediatrics Wayne State University School of MedicineDetroitMIUSA

Acute myeloid leukemia(AML)is the most common form of acute leukemia in adults and the second most common form of acute leukemia in *** this,very little improvement in survival rates has been achieved over the past few *** is partially due to the heterogeneity of AML and the need for more targeted therapeutics than the traditional cytotoxic chemotherapies that have been a mainstay in therapy for the past 50 *** the past 20 years,research has been diversifying the approach to treating AML by investigating molecular pathways uniquely relevant to AML cell proliferation and *** we review the development of novel therapeutics in targeting apoptosis,receptor tyrosine kinase(RTK)signaling,hedgehog(HH)pathway,mitochondrial function,DNA repair,and c-Myc *** has been an impressive effort into better understanding the diversity of AML cell characteristics and here we highlight important preclinical studies that have supported therapeutic development and continue to promote new ways to target AML *** addition,we describe clinical investigations that have led to FDA approval of new targeted AML therapies and ongoing clinical trials of novel therapies targeting AML survival *** also describe the complexity of targeting leukemia stem cells(LSCs)as an approach to addressing relapse and remission in AML and targetable pathways that are unique to LSC *** comprehensive review details what we currently understand about the signaling pathways that support AML cell survival and the exceptional ways in which we disrupt them.

关键词： myeloid approach approval