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1.
Zhonghua Nei Ke Za Zhi ; 58(11): 819-822, 2019 Nov 01.
Artigo em Chinês | MEDLINE | ID: mdl-31665857

RESUMO

The efficacy and safety of co-transplantation of unrelated donor peripheral blood stem cells (UD-PBSCs) combined with umbilical cord mesenchymal stem cells (UC-MSCs) in refractory severe aplastic anemia-Ⅱ(RSAA-Ⅱ) were analyzed retrospectively. Fifteen patients with RSAA-Ⅱ underwent UD-PBSCs and UC-MSCs co-transplantation, among whom 14 cases had hematopoietic reconstitution without severe graft versus-host disease (GVHD). The 5-year overall survival rate was 78.57%. Combination of UD-PBSCs and UC-MSCs transplantation could be a safe and effective option for RSAA-Ⅱ.


Assuntos
Anemia Aplástica/cirurgia , Transplante de Células-Tronco Hematopoéticas/métodos , Células-Tronco Hematopoéticas/fisiologia , Cordão Umbilical/fisiologia , Doadores não Relacionados , Anemia Aplástica/imunologia , Anemia Aplástica/mortalidade , Anemia Aplástica/patologia , China/epidemiologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Células-Tronco Hematopoéticas/imunologia , Humanos , Células-Tronco Mesenquimais , Células-Tronco de Sangue Periférico , Estudos Retrospectivos , Taxa de Sobrevida , Doadores de Tecidos , Condicionamento Pré-Transplante/métodos , Resultado do Tratamento , Cordão Umbilical/imunologia
2.
Rinsho Ketsueki ; 60(9): 1056-1062, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597827

RESUMO

The hematopoietic stem cells, defined as blood stem cells with self-replication ability and multipotency, are key to successful hematopoietic stem cell transplantation. With the history of transplantation in the past 60 years and advances in stem cell technologies, our understanding of the hematopoietic system has deepened. However, the molecular mechanisms of self-renewal and pluripotency, which are the essence of the hematopoietic stem cells, remain poorly understood. One reason is that the identification/purification methods of the hematopoietic stem cells, particularly the long-term hematopoietic stem cells capable of lifelong self-renewal, is technically difficult owing to their scarcity in the bone marrow and has not been established to this date. Considering that a long-lasting blood production after hematopoietic stem cell transplantation is crucial, it is essential to understand the biology of the long-term hematopoietic stem cells not only scientifically but also clinically. This review describes the scientific and clinical significance of the long-term hematopoietic stem cells by showing the results of the latest researches in the introduction of hematopoietic stem cell identification/purification history.


Assuntos
Separação Celular , Células-Tronco Hematopoéticas/citologia , Medula Óssea , Células da Medula Óssea/citologia , Transplante de Células-Tronco Hematopoéticas , Humanos
3.
Rinsho Ketsueki ; 60(9): 1075-1083, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597830

RESUMO

The mechanism underlying production of various types of blood cells from hematopoietic stem and progenitor cells has been a central theme in hematology. Conventionally, hematopoietic cell populations are analyzed by cell surface markers to judge cell types and differentiation stages, and by transplantation assays to assess differentiation potential. Recently, however, next-generation sequencing technology has enabled single-cell transcriptome and epigenome analyses and cell barcoding-based lineage tracing during unperturbed hematopoiesis. These innovative assays revealed that each cell population is extensively heterogenous. Many cells within hematopoietic stem cell populations may not be multipotent, and conversely, hematopoietic progenitor cells often display self-renewal capacity. Moreover, cells tend to make their lineage choice much earlier than previously thought. Altogether, these results challenge the current hierarchical differentiation models and propose new continuous models. Single-cell analyses are expected to greatly contribute to our understanding of normal and abnormal hematopoiesis and to the development of new therapies for blood disorders.


Assuntos
Hematopoese , Células-Tronco Hematopoéticas/citologia , Análise de Célula Única , Diferenciação Celular , Linhagem da Célula , Epigenômica , Humanos , Transcriptoma
4.
Mol Biol (Mosk) ; 53(5): 711-724, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661473

RESUMO

Blood is extremely important for a multicellular organism: it connects all organs and tissues, supplies them with nutrients and oxygen, removes carbon dioxide and metabolic products, maintains homeostasis, and provides protection against infections. That is why studies on blood have always drawn a great deal of attention. In ancient times, it was believed that the soul was in the blood and that it sometimes "sank into the stomach." Initially, the study of blood was limited to morphological methods, to which physiological and cellular research were added in the twentieth century. With their help, researchers established that mature blood cells are formed from a rare population of hematopoietic stem cells (HSCs), which are located in the bone marrow. The development of molecular biology methods and their combination with classical physiological ones allowed a breakthrough in understanding the structure of the hematopoietic system, which changed our understanding not only of hematopoiesis but also about the nature of adult stem cells. This review describes the molecular assays used in experimental hematology, and how their application has gradually been expanding our knowledge of blood formation and continues to provide new information about it.


Assuntos
Hematopoese , Sistema Hematopoético/citologia , Sistema Hematopoético/fisiologia , Biologia Molecular/métodos , Células-Tronco Adultas/citologia , Medula Óssea , Células-Tronco Hematopoéticas/citologia , Humanos
5.
Washington, D. C.; PAHO; 2019-09-20. (PAHO/HSS/19-004).
em Inglês | PAHO-IRIS | ID: phr-51558

RESUMO

The aim of this document is to highlight the progress made with regard to advanced therapy products, the risks associated with such products, and the regulatory challenges they pose for Member States with a view to strengthening regulatory systems. The document is also a call to action for governments to consider the development of standards and rules for regulating these products in order to control the use of unapproved therapies and prevent risks to the population. As discussed, there are cross-cutting regulatory principles that should be implemented by any regulatory body that plans to undertake the regulation and oversight of advanced therapy products.


Assuntos
Assistência Farmacêutica , Sistemas de Saúde , Farmácia , Farmacovigilância , Células-Tronco Hematopoéticas , Sistema Imunitário , Sistemas Sanguíneo e Imunológico
6.
Washington, D. C.; OPS; 2019-09-20. (OPS/HSS/19-004).
em Espanhol | PAHO-IRIS | ID: phr-51557

RESUMO

Este documento pretende resaltar los avances y riesgos de los productos de terapias avanzadas y los desafíos regulatorios que enfrentan los estados miembros respecto a estos productos, a fin de promover el fortalecimiento de los sistemas regulatorios. Igualmente, es un llamado para que los gobiernos consideren el desarrollo de normas y reglamentos que regulen estos medicamentos a fin de controlar el uso de terapias no aprobadas y prevenir el riesgo de la población. Como se menciona en este documento existen principios regulatorios transversales que deben estar implementados por un ente regulatorio que prevé hacerse cargo de la regulación y fiscalización de productos de terapia avanzada.


Assuntos
Sistemas de Saúde , Farmácia , Assistência Farmacêutica , Farmacovigilância , Células-Tronco Hematopoéticas , Sistema Imunitário , Sistemas Sanguíneo e Imunológico
7.
Adv Exp Med Biol ; 1169: 195-211, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31487025

RESUMO

Hematopoietic stem cells (HSCs) maintain lifelong production of mature blood cells and regenerate the hematopoietic system after cytotoxic injury. Use of expanding cell surface marker panels and advanced functional analyses have revealed the presence of several immunophenotypically different HSC subsets with distinct self-renewal and repopulating capacity and bias toward selective lineage differentiation. This chapter summarizes current understanding of the phenotypic and functional heterogeneity within the HSC pool, with emphasis on the immunophenotypes and functional features of several known HSC subsets, and their roles in steady-state and emergency hematopoiesis, and in aging. The chapter also highlights some of the future research directions to elucidate further the biology and function of different HSC subsets in health and disease states.


Assuntos
Diferenciação Celular , Hematopoese , Células-Tronco Hematopoéticas , Animais , Humanos
8.
N Engl J Med ; 381(13): 1240-1247, 2019 09 26.
Artigo em Inglês | MEDLINE | ID: mdl-31509667

RESUMO

The safety of CRISPR (clustered regularly interspaced short palindromic repeats)-based genome editing in the context of human gene therapy is largely unknown. CCR5 is a reasonable but not absolutely protective target for a cure of human immunodeficiency virus type 1 (HIV-1) infection, because CCR5-null blood cells are largely resistant to HIV-1 entry. We transplanted CRISPR-edited CCR5-ablated hematopoietic stem and progenitor cells (HSPCs) into a patient with HIV-1 infection and acute lymphoblastic leukemia. The acute lymphoblastic leukemia was in complete remission with full donor chimerism, and donor cells carrying the ablated CCR5 persisted for more than 19 months without gene editing-related adverse events. The percentage of CD4+ cells with CCR5 ablation increased by a small degree during a period of antiretroviral-therapy interruption. Although we achieved successful transplantation and long-term engraftment of CRISPR-edited HSPCs, the percentage of CCR5 disruption in lymphocytes was only approximately 5%, which indicates the need for further research into this approach. (Funded by the Beijing Municipal Science and Technology Commission and others; ClinicalTrials.gov number, NCT03164135.).


Assuntos
Sistemas CRISPR-Cas , Edição de Genes/métodos , Infecções por HIV/terapia , HIV-1 , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas , Receptores CCR5/genética , Adulto , Antirretrovirais/uso terapêutico , Contagem de Células Sanguíneas , Contagem de Linfócito CD4 , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , HIV-1/genética , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Carga Viral
9.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1046-1052, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418355

RESUMO

OBJECTIVE: To investigate the relationship between the expression of lysosomal membrane proteins LAMP1, TPC1 and TPC2 in acute myeloid leukemia (AML) cells and clinical indications of AML and to explore the possible role in the genesis and development of AML and clinical significance. METHODS: Real-time quantitative PCR was used to detect the mRNA expression of LAMP1, TPC1 and TPC2 in AML cell lines (HL-60, NB4) and 57 patients with acute myeloid leukemia (including 44 initially treated patients and 13 relapsed and refractory patients). The relationship of mRNA expression levels with clinical indicators and post-chemotherapy remission was analyzed. RESULTS: Compared with CD34+ hematopoietic stem cells (HSC), the expression levels of LAMP1 and TPC1 in AML cell lines HL-60 and NB4 significantly increased, while the expression level of TPC2 was not significantly different. The expression levels of LAMP1, TPC1 and TPC2 in bone marrow mononuclear cells (BMMNC) of AML patients were higher than those in normal human BMMNC (P<0.05), and the expression levels of LAMP1, TPC1 and TPC2 in CD34+ primary AML cells(CD34+ primary cells in the patient's bone marrow >90%) were also high. There was no significant difference in the expression of LAMP1, TPC1 and TPC2 between CD34+HSC of patients with AML and relapsed/refractory patients (P>0.05). No correlation was found between age, sex and genotype and expression of membrane proteins (P>0.05). The expression levels of LAMP1 and TPC1 positively correlated with the number of white blood cells in peripheral blood of patients (P<0.01). LAMP1 and TPC2 were found to be associated with remission after a course of chemotherapy in newly diagnosed patients. Initially treated patients with high expression of LAMP1 in the bone marrow not easily relieved after one course of chemotherapy. Patients with high expression of TPC2 in the bone marrow more likely to be relieved after one course of chemotherapy. CONCLUSION: The mRNA of the three membrane proteins are highly expressed in AML patients, and LAMP1 and TPC1 are risk factors for AML disease progression. High expression of TPC2 is beneficial for chemotherapy of patients with newly diagnosed AML.


Assuntos
Leucemia Mieloide Aguda , Medula Óssea , Células da Medula Óssea , Células-Tronco Hematopoéticas , Humanos , Glicoproteínas de Membrana Associadas ao Lisossomo
10.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1265-1271, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418391

RESUMO

OBJECTIVE: To explore the effect of bone morphogenetic protein 4(BMP4) on the cell cycle and apoptosis of hemaropoictic stem and progenitor cells (HSPC) in conditions of 5-fluorouracil (5-FU)-inducing bone marrow suppression and stress hemogenesis, and its possible mechanism. METHODS: The C57BL transgenic mice with BMP4 overexpression were established and were enrolled in transgenic group (BMP4 group), at the same time the wild type mice matching in age, sex and body weight were selected and were enrolled in control group (WT group). The bone marrow suppression was induced by injection with 5-FU in dose of 150 mg/kg, then the nucleated cells were isolated from bone marrow. After the HSPCs were markered with C-kit/sca-1 fluorescent antibodies, the changes of cell cycle and apoptosis of HSPC were detected by Aunexin V/PI and Ki67/DAPI double staining; the cell cycle-essociated hemotopoietic regulatory factors were detected by RT-qPCR. RESULTS: Under physiologic status, there were no significant differences in cell cycle and apoptotic rate of HSPC between WT group and BMP-4 group. After the bone marrow was suppressed, the ratio of HSPC at G0 phase in BMP4 group significantly decreased(P<0.05); the apoptosis rate of HSPC significantly increased(P<0.05); the mRNA expression levels of hypoxia-inducing factor Hif-1α and chemotactic factor CXCL12 in stroma of BMP4 group were down-regulated significanfly(P<0.05). CONCLUSION: Under non-physiologic conditions such as stress hemogenesis or bone marrow suppression, the up-regulation of BMP4 can promote HSPC into cell cycle and apoptosis of HSPC, moreover, the BMP4 may play a regulatory role for cell cycle of HSPC through direct or indirect down-regulation of Hif-1α and CXCL-12 expressions.


Assuntos
Células-Tronco Hematopoéticas , Animais , Antineoplásicos , Apoptose , Proteína Morfogenética Óssea 4 , Ciclo Celular , Camundongos , Camundongos Endogâmicos C57BL
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(4): 1272-1276, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31418392

RESUMO

OBJECTIVE: To explore the method of isolation, purification and differentiation of hematopoietic stem cells (HSCs) into dendritic cells (DC) in lung tissue of mouse, so as to provide theoretical basis and experimental methods for the study of hematopoietic stem cells in mouse lung tissue. METHODS: Lung tissues of 4 male C57 mice were digested, separated and purified into mononuclear cells by type I collagenase, type I DNA enzyme and lymphocyte isolation solution. Lin-Sca-1+c-Kit+ cells, which are hematopoietic stem cells (HSCs) were identified and sorted by flow cytometry. Stem cell factor (SCF) and interleukin 3 (IL-3) were added in the obtained HSCs to promote cell proliferation. After discontinuation of SCF and IL-3, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-4 were added to induce differentiation of HSCs into DCs, and lipopolysaccharide (LPS) was added to promote cell maturation. The morphology of DCs was observed under inverted microscope, the expression of CD80, CD86, CD11c and MII-II on the surface of DCs was analyzed by flow cytometry, and the expression level of IL-12 was detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: 2419.67±247.59 HSCs were collected from lung tissue mononuclear cells of 4 mice identified by flow cytometry with purity: (7.16±0.43)%. HSCs were amplified 62.34±3.23 times by induction with SCF and IL-3 for 7 days. After induction culture for 15 days, mature dendritic cells were obtained with typical dendrites on the cell surface, the DC expressed dendritic cell-specific surface molecules CDllc (92.62±3.68)%,MHC-II (83.89±6.28)%, CD80 (75.96±5.13)%, CD86(72.07±4.38)%, and the expression level of IL-12 was 136.12±16.59 pg/ml detected by ELISA. CONCLUSION: There are HSCs in lung tissue, which can be transformed into DCs by cytokine induction and proliferation.


Assuntos
Células Dendríticas , Células-Tronco Hematopoéticas , Animais , Diferenciação Celular , Células Cultivadas , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Masculino , Camundongos
12.
Nature ; 571(7765): 355-360, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31270458

RESUMO

Defining the transcriptomic identity of malignant cells is challenging in the absence of surface markers that distinguish cancer clones from one another, or from admixed non-neoplastic cells. To address this challenge, here we developed Genotyping of Transcriptomes (GoT), a method to integrate genotyping with high-throughput droplet-based single-cell RNA sequencing. We apply GoT to profile 38,290 CD34+ cells from patients with CALR-mutated myeloproliferative neoplasms to study how somatic mutations corrupt the complex process of human haematopoiesis. High-resolution mapping of malignant versus normal haematopoietic progenitors revealed an increasing fitness advantage with myeloid differentiation of cells with mutated CALR. We identified the unfolded protein response as a predominant outcome of CALR mutations, with a considerable dependency on cell identity, as well as upregulation of the NF-κB pathway specifically in uncommitted stem cells. We further extended the GoT toolkit to genotype multiple targets and loci that are distant from transcript ends. Together, these findings reveal that the transcriptional output of somatic mutations in myeloproliferative neoplasms is dependent on the native cell identity.


Assuntos
Genótipo , Mutação , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Neoplasias/genética , Neoplasias/patologia , Transcriptoma/genética , Animais , Antígenos CD34/metabolismo , Calreticulina/genética , Linhagem Celular , Proliferação de Células , Células Clonais/classificação , Células Clonais/metabolismo , Células Clonais/patologia , Endorribonucleases/metabolismo , Hematopoese/genética , Células-Tronco Hematopoéticas/classificação , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Camundongos , Modelos Moleculares , Transtornos Mieloproliferativos/classificação , NF-kappa B/metabolismo , Neoplasias/classificação , Células-Tronco Neoplásicas/citologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Resposta a Proteínas não Dobradas/genética
13.
Nat Biotechnol ; 37(7): 810-818, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31267104

RESUMO

A major challenge for stem cell engineering is achieving a holistic understanding of the molecular networks and biological processes governing cell differentiation. To address this challenge, we describe a computational approach that combines gene expression analysis, previous knowledge from proteomic pathway informatics and cell signaling models to delineate key transitional states of differentiating cells at high resolution. Our network models connect sparse gene signatures with corresponding, yet disparate, biological processes to uncover molecular mechanisms governing cell fate transitions. This approach builds on our earlier CellNet and recent trajectory-defining algorithms, as illustrated by our analysis of hematopoietic specification along the erythroid lineage, which reveals a role for the EGF receptor family member, ErbB4, as an important mediator of blood development. We experimentally validate this prediction and perturb the pathway to improve erythroid maturation from human pluripotent stem cells. These results exploit an integrative systems perspective to identify new regulatory processes and nodes useful in cell engineering.


Assuntos
Engenharia Celular , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Pluripotentes Induzidas/fisiologia , Biologia de Sistemas/métodos , Algoritmos , Animais , Antígenos CD34/genética , Antígenos CD34/metabolismo , Diferenciação Celular , Linhagem da Célula , Proliferação de Células , Biologia Computacional/métodos , Eritrócitos , Eritropoese , Citometria de Fluxo , Regulação da Expressão Gênica , Redes Reguladoras de Genes , Humanos , Camundongos , Receptor ErbB-4/metabolismo , Transdução de Sinais , Peixe-Zebra
14.
Nat Biotechnol ; 37(8): 945-952, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31359006

RESUMO

Engineered nucleases have gained broad appeal for their ability to mediate highly efficient genome editing. However the specificity of these reagents remains a concern, especially for therapeutic applications, given the potential mutagenic consequences of off-target cleavage. Here we have developed an approach for improving the specificity of zinc finger nucleases (ZFNs) that engineers the FokI catalytic domain with the aim of slowing cleavage, which should selectively reduce activity at low-affinity off-target sites. For three ZFN pairs, we engineered single-residue substitutions in the FokI domain that preserved full on-target activity but showed a reduction in off-target indels of up to 3,000-fold. By combining this approach with substitutions that reduced the affinity of zinc fingers, we developed ZFNs specific for the TRAC locus that mediated 98% knockout in T cells with no detectable off-target activity at an assay background of ~0.01%. We anticipate that this approach, and the FokI variants we report, will enable routine generation of nucleases for gene editing with no detectable off-target activity.


Assuntos
Clivagem do DNA , Edição de Genes/métodos , Linfócitos T , Sequência de Bases , DNA/genética , DNA/metabolismo , Citometria de Fluxo , Células-Tronco Hematopoéticas , Humanos , Células K562 , Domínios Proteicos , RNA Mensageiro
15.
Ann Hematol ; 98(9): 2063-2072, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31312928

RESUMO

Rigosertib is a novel multi-kinase inhibitor, which has clinical activity towards leukemic progenitor cells of patients with high-risk myelodysplastic syndromes (MDS) after failure or progression on hypomethylating agents. Since the bone marrow microenvironment plays an important role in MDS pathogenesis, we investigated the impact of rigosertib on cellular compartments within the osteo-hematopoietic niche. Healthy C57BL/6J mice treated with rigosertib for 3 weeks showed a mild suppression of hematopoiesis (hemoglobin and red blood cells, both - 16%, p < 0.01; white blood cells, - 34%, p < 0.05; platelets, - 38%, p < 0.05), whereas there was no difference in the number of hematopoietic stem cells in the bone marrow. Trabecular bone mass of the spine was reduced by rigosertib (- 16%, p = 0.05). This was accompanied by a lower trabecular number and thickness (- 6% and - 10%, respectively, p < 0.05), partly explained by the increase in osteoclast number and surface (p < 0.01). Milder effects of rigosertib on bone mass were detected in an MDS mouse model system (NHD13). However, rigosertib did not further aggravate MDS-associated cytopenia in NHD13 mice. Finally, we tested the effects of rigosertib on human mesenchymal stromal cells (MSC) in vitro and demonstrated reduced cell viability at nanomolar concentrations. Deterioration of the hematopoietic supportive capacity of MDS-MSC after rigosertib pretreatment demonstrated by decreased number of colony-forming units, especially in the monocytic lineage, further supports the idea of disturbed crosstalk within the osteo-hematopoietic niche mediated by rigosertib. Thus, rigosertib exerts inhibitory effects on the stromal components of the osteo-hematopoietic niche which may explain the dissociation between anti-leukemic activity and the absence of hematological improvement.


Assuntos
Glicina/análogos & derivados , Hematopoese/efeitos dos fármacos , Células-Tronco Hematopoéticas , Células-Tronco Mesenquimais , Síndromes Mielodisplásicas , Nicho de Células-Tronco/efeitos dos fármacos , Sulfonas/farmacologia , Animais , Glicina/farmacologia , Células-Tronco Hematopoéticas/metabolismo , Células-Tronco Hematopoéticas/patologia , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/patologia , Camundongos , Camundongos Transgênicos , Síndromes Mielodisplásicas/tratamento farmacológico , Síndromes Mielodisplásicas/metabolismo , Síndromes Mielodisplásicas/patologia
16.
Rinsho Ketsueki ; 60(6): 680-690, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31281161

RESUMO

Recent progress in whole genome sequencing has identified recurrent somatic mutations in the additional sex combs like 1 (ASXL1) gene in a variety of hematological disorders and even in premalignant conditions. However, the molecular mechanisms regarding the contribution of ASXL1 mutation to the pathogenesis of premalignant conditions remain largely unelucidated. Thus, we investigated the biological effects of mutant Asxl1 using newly-generated knock-in (KI) mice. Heterozygous mutant KI mice developed phenotypes resembling human low-risk myelodysplastic syndromes (MDS), and some of them developed an MDS/myeloproliferative neoplasm-like disease after a long latency. The H2AK119ub1 level around the promoter region of p16Ink4a was significantly decreased in KI hematopoietic stem cells (HSCs), suggesting perturbation of Bmi1-driven H2AK119ub1 histone modification by mutant Asxl1. The mutant Asxl1 failed to interact with Bmi1, although wild type ASXL1 protein did not. When p16Ink4a expression was depleted in Asxl1 KI mice, the HSC pool was restored, and apoptosis was ameliorated in HSCs. These findings demonstrate that the loss of protein interaction between mutant Asxl1 and Bmi1 affected the activity of Prc1. The subsequent derepression of p16Ink4a by aberrant histone ubiquitination could induce cellular senescence, resulting in low-risk MDS-like phenotypes in heterozygous Asxl1 KI mice.


Assuntos
Mutação , Síndromes Mielodisplásicas/genética , Proteínas Repressoras/genética , Animais , Modelos Animais de Doenças , Técnicas de Introdução de Genes , Células-Tronco Hematopoéticas , Histonas/metabolismo , Camundongos , Fenótipo , Complexo Repressor Polycomb 1/genética , Proteínas Proto-Oncogênicas/genética , Ubiquitinação
17.
Adv Exp Med Biol ; 1143: 1-39, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31338813

RESUMO

Hematopoietic stem cells (HSCs) and leukemic stem cells (LSCs) utilize many of the same signaling pathways for their maintenance and survival. In this review, we will focus on several signaling pathways whose roles have been extensively studied in both HSCs and LSCs. Our main focus will be on the PI3K/AKT/mTOR pathway and several of its regulators and downstream effectors. We will also discuss several other signaling pathways of particular importance in LSCs, including the WNT/ß-catenin pathway, the NOTCH pathway, and the TGFß pathway. For each of these pathways, we will emphasize differences in how these pathways operate in LSCs, compared to their function in HSCs, to highlight opportunities for the specific therapeutic targeting of LSCs. We will also highlight areas of crosstalk between multiple signaling pathways that may affect LSC function.


Assuntos
Células-Tronco Hematopoéticas , Células-Tronco Neoplásicas , Transdução de Sinais , Células-Tronco Hematopoéticas/fisiologia , Humanos , Células-Tronco Neoplásicas/fisiologia , Proteína Oncogênica v-akt/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Serina-Treonina Quinases TOR/metabolismo
18.
Adv Exp Med Biol ; 1143: 59-74, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31338815

RESUMO

One of the bottlenecks of the treatments for malignant hematopoietic disorders is the unavailability of sufficient amount of hematopoietic stem cells (HSCs). HSCs are considered to be originated from the aorta-gonad-mesonephros and gradually migrates into fetal liver and resides in a unique microenvironment/niche of bone marrow. Although many intrinsic and extrinsic factors (niche components) are reported to be involved in the origination, maturation, migration, and localization of HSCs at different developmental stages, the detailed molecular mechanisms still remain largely unknown. Previous studies have shown that intrinsic metabolic networks may be critical for the cell fate determinations of HSCs. For example, HSCs mainly utilize glycolysis as the main energy sources; oxidative phosphorylation is required for the homeostasis of HSCs; lipid or amino acid metabolisms may also sustain HSC stemness. Mechanistically, lots of regulatory pathways, such as MEIS1/HIF1A and PI3K/AKT/mTOR signaling, are found to fine-tune the different nutrient metabolisms and cell fate commitments of HSCs. However, more efforts are required for the optimization and establishment of precise metabolic techniques specific for the HSCs with relatively rare cell frequency and understanding of the basic metabolic properties and their underlying regulatory mechanisms of different nutrients (such as glucose) during the different developmental stages of HSCs.


Assuntos
Diferenciação Celular , Células-Tronco Hematopoéticas , Transdução de Sinais , Medula Óssea/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos
19.
Adv Exp Med Biol ; 1143: 129-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31338818

RESUMO

The relationship of the homing of normal hematopoietic stem cells (HSC) in the bone marrow to specific environmental conditions, referred to as the stem cell niche (SCN), has been intensively studied over the last three decades. These conditions include the action of a number of molecular and cellular players, as well as critical levels of nutrients, oxygen and glucose in particular, involved in energy production. These factors are likely to act also in leukemias, due to the strict analogy between the hierarchical structure of normal hematopoietic cell populations and that of leukemia cell populations. This led to propose that leukemic growth is fostered by cells endowed with stem cell properties, the leukemia stem cells (LSC), a concept readily extended to comprise the cancer stem cells (CSC) of solid tumors. Two alternative routes have been proposed for CSC generation, that is, the oncogenic staminalization (acquisition of self-renewal) of a normal progenitor cell (the "CSC in normal progenitor cell" model) and the oncogenic transformation of a normal (self-renewing) stem cell (the "CSC in normal stem cell" model). The latter mechanism, in the hematological context, makes LSC derive from HSC, suggesting that LSC share SCN homing with HSC. This chapter is focused on the availability of oxygen and glucose in the regulation of LSC maintenance within the SCN. In this respect, the most critical aspect in view of the outcome of therapy is the long-term maintenance of the LSC subset capable to sustain minimal residual disease and the related risk of relapse of disease.


Assuntos
Hipóxia Celular , Leucemia Mieloide Aguda , Leucemia , Células-Tronco Neoplásicas , Glucose/metabolismo , Células-Tronco Hematopoéticas , Humanos , Oxigênio/metabolismo , Nicho de Células-Tronco
20.
Adv Exp Med Biol ; 1143: 147-171, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31338819

RESUMO

In humans, hematopoietic stem cells (HSCs) adopt unique responsive pathways counteracting with the DNA-damaging assaults to weigh the balance between the maintenance of normal stem cell poor for whole-life blood regeneration and the transformation to leukemia stem cells (LSCs) for leukemia initiation. LSCs also take actions of combating with the attack launched by externally therapeutic drugs that can kill most leukemic cells, to avoid extermination and promote disease relapse. Therefore, the collection of knowledge about all these underlined mechanisms would present a preponderance for later studies. In this chapter, the universal DNA damage response (DDR) mechanisms were firstly introduced, and then DDR of HSCs were presented focusing on the DNA double-strand breaks in the quiescent state of HSCs, which poses a big advantage in promoting its transformation into preleukemic HSCs. Lastly, the DDR of LSCs were summarized based on the major outcomes triggered by different pathways in specific leukemia, upon which some aspects for future investigations were envisioned under our currently limited scope of knowledge.


Assuntos
Dano ao DNA , Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Células-Tronco Neoplásicas , Divisão Celular , Células-Tronco Hematopoéticas/patologia , Humanos , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/patologia
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