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1.
Rinsho Ketsueki ; 60(9): 1046-1055, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597826

RESUMO

Human iPS cells are somatic cells reprogrammed to the pluripotent state. Because of their pluripotent nature, iPS cells are now commonly used to model several developmental processes including hematopoiesis in vitro. The in vitro models can be used to study the mechanisms regulating not only normal hematopoiesis but also hematological diseases ranging from monogenic congenital disorders to genetically multifactorial malignancies. Those disease models can also be used to investigate novel treatments through procedures including high throughput drug screening. The possible clinical applications of iPS cell-derived hematopoietic cells include immunotherapy with T lymphocytes, NK cells and macrophages, and transfusion therapy with platelets and red blood cells. Platelets have now been produced from iPS cells in quantities sufficient for clinical use. By developing expandable immortalized megakaryocyte cell lines (imMKCLs), several novel drugs and turbulence-incorporated bioreactors, efficient and scalable generation of platelets was achieved. This review summarizes the current status of iPS cell research in hematopoiesis with details on iPS cell-derived platelets.


Assuntos
Plaquetas/citologia , Terapia Baseada em Transplante de Células e Tecidos , Células-Tronco Pluripotentes Induzidas/citologia , Diferenciação Celular , Eritrócitos , Hematopoese , Humanos , Imunoterapia , Células Matadoras Naturais , Macrófagos , Megacariócitos , Linfócitos T
2.
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
3.
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
4.
Georgian Med News ; (292-293): 87-92, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31560670

RESUMO

Hematological disorders caused by radiation remain the most challenging problem of the last decades. Environmental radiation, as well as medical application of radiation causes serious problems especially from the point of view of blood formation and passage of blood functional cells. Bone marrow emptying followed by the rise of immature cells in the bloodstream is the main pathology that must be eliminated. The importance of the issue is well recognized by all investigators. Opening of agents for regulation of spontaneous regeneration of hematopoietic cell lines is of prime importance in cancer treatment. Ubiquitin is a globular protein of eukaryotic cells. It is involved in regulation of cell cycle. Recently we studied the influence of extracellular ubiquitin on regeneration of leukopoiesis. Interestingly what is its effect on erythropoietic cell lines? Erythrocytes are more resistant to irradiation, than nucleic cells. Their depletion-elevation picks during blood regeneration clearly reveal low sharpness. Nevertheless, depletion of erythropoietic cells if not treated, may cause short- and long-term side effects. We studied the influence of intraperitoneally injected ubiquitin on the process of spontaneous regeneration of erythropoietic cell lines of bone marrow (BM) and peripheral blood (PB) after irradiation in mice. The source of radiation was 137Cs with dose rate 1Gy/min., the duration of exposure 3 min and 5 min. Nonlinear white mice of 22±2 gr. were used for experiment. Animals were divided into five groups (6 animals in each group): the first control group of intact mice; the second test group of mice irradiated by the sublethal dose of 3Gy; the third test group of mice irradiated by 3Gy intraperitoneally injected by ubiquitin by the dose of 100µg/ml at the 72 hour point after irradiation; the fourth test group of mice irradiated by the dose of LD50 5Gy; the fifth test group of mice irradiated by 5Gy intraperitoneally injected by ubiquitin at the 72 hour point after irradiation. PB and BM samples from the control group and the test groups of mice have been taken every 24 hours after irradiation during 7 days. Microscopy and statistical methods have been implicated for calculation of cell count of PB and BM. Analyzing the results we concluded that Ubiquitin prevents depletion-elevation picks of erythrocytes and erythroblasts regardless of the severity of damage caused by different doses of radiation indicating normalization of the regeneration process after irradiation. The study is important for opening new therapeutic agents for normalization of regeneration hematopoiesis after irradiation.


Assuntos
Células da Medula Óssea/efeitos dos fármacos , Radioisótopos de Césio , Hematopoese/efeitos dos fármacos , Lesões Experimentais por Radiação , Regeneração/efeitos dos fármacos , Ubiquitina/farmacologia , Animais , Ciclo Celular/efeitos da radiação , Camundongos , Ubiquitina/administração & dosagem
5.
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
7.
Genes Dev ; 33(17-18): 1117-1135, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31481536

RESUMO

T-cell development in mammals is a model for lineage choice and differentiation from multipotent stem cells. Although T-cell fate choice is promoted by signaling in the thymus through one dominant pathway, the Notch pathway, it entails a complex set of gene regulatory network and chromatin state changes even before the cells begin to express their signature feature, the clonal-specific T-cell receptors (TCRs) for antigen. This review distinguishes three developmental modules for T-cell development, which correspond to cell type specification, TCR expression and selection, and the assignment of cells to different effector types. The first is based on transcriptional regulatory network events, the second is dominated by somatic gene rearrangement and mutation and cell selection, and the third corresponds to establishing a poised state of latent regulator priming through an unknown mechanism. Interestingly, in different lineages, the third module can be deployed at variable times relative to the completion of the first two modules. This review focuses on the gene regulatory network and chromatin-based kinetic constraints that determine activities of transcription factors TCF1, GATA3, PU.1, Bcl11b, Runx1, and E proteins in the primary establishment of T-cell identity.


Assuntos
Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Linfócitos T/citologia , Animais , Diferenciação Celular/genética , Linhagem da Célula , Cromatina/metabolismo , Redes Reguladoras de Genes , Hematopoese , Linfócitos T/metabolismo , Timo/citologia , Timo/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
8.
Cancer Sci ; 110(10): 3375-3381, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31436356

RESUMO

Cell-free DNA (cfDNA) analysis to detect circulating tumor DNA has been focused on monitoring malignant lymphomas. However, clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations can also be detected by cfDNA analysis. Our aim is to investigate the origin of mutations detected in cfDNA among B-cell lymphoma patients. MYD88/CD79B, DNMT3A, and TP53 were chosen as genes of interest, representing each of the following categories: lymphoma driver genes, CHIP-related genes, and genes shared between lymphoma and CHIP. Seventy-five B-cell lymphoma patients were included in this retrospective study. Serum cfDNAs at time of complete metabolic response (CMR) were sequenced for TP53 (N = 75) and DNMT3A (N = 49). MYD88 p.L265P and CD79B p.Y196C/H mutations were analyzed in diffuse large B-cell lymphoma (DLBCL) patients whose tumor samples were available (N = 29). Two and seven mutations in TP53 and DNMT3A, respectively, were detected in cfDNA at CMR. These mutations were detected in either bone marrow mononuclear cells (BMMC) or PBMC. Although four DNMT3A mutations were also detected in tumors, median variant allele frequencies in the tumors (<1.0%) were significantly lower than those in both BMMC (6.1%) and serum (5.2%) obtained before the therapy. Conversely, five MYD88 and three CD79B mutations detected in tumors were confirmed in cfDNA before therapy, but not in BMMC nor in cfDNA at CMR. Thus, all TP53 and DNMT3A mutations detected in cfDNA at remission seemed to originate from CHIP rather than from residual disease. Results of liquid biopsy should be carefully interpreted, especially in genes shared between lymphomas and CHIP.


Assuntos
Células Clonais/química , DNA (Citosina-5-)-Metiltransferases/genética , Hematopoese , Linfoma de Células B/genética , Mutação , Proteína Supressora de Tumor p53/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Células da Medula Óssea/química , Ácidos Nucleicos Livres/genética , Feminino , Frequência do Gene , Humanos , Leucócitos Mononucleares/química , Biópsia Líquida , Masculino , Pessoa de Meia-Idade , Monócitos/química , Indução de Remissão , Estudos Retrospectivos , Análise de Sequência de DNA/métodos
9.
Nat Biotechnol ; 37(8): 925-936, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31375813

RESUMO

Understanding complex tissues requires single-cell deconstruction of gene regulation with precision and scale. Here, we assess the performance of a massively parallel droplet-based method for mapping transposase-accessible chromatin in single cells using sequencing (scATAC-seq). We apply scATAC-seq to obtain chromatin profiles of more than 200,000 single cells in human blood and basal cell carcinoma. In blood, application of scATAC-seq enables marker-free identification of cell type-specific cis- and trans-regulatory elements, mapping of disease-associated enhancer activity and reconstruction of trajectories of cellular differentiation. In basal cell carcinoma, application of scATAC-seq reveals regulatory networks in malignant, stromal and immune cells in the tumor microenvironment. Analysis of scATAC-seq profiles from serial tumor biopsies before and after programmed cell death protein 1 blockade identifies chromatin regulators of therapy-responsive T cell subsets and reveals a shared regulatory program that governs intratumoral CD8+ T cell exhaustion and CD4+ T follicular helper cell development. We anticipate that scATAC-seq will enable the unbiased discovery of gene regulatory factors across diverse biological systems.


Assuntos
Células da Medula Óssea/metabolismo , Cromatina/química , Análise de Célula Única/métodos , Linfócitos T/metabolismo , Linhagem Celular , Simulação por Computador , Regulação da Expressão Gênica , Hematopoese , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucócitos Mononucleares , Fatores de Transcrição/metabolismo
11.
Rinsho Ketsueki ; 60(7): 818-823, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31391372

RESUMO

Myelodysplastic syndromes (MDS), a group of heterogeneous hematopoietic disorders, are characterized by multi-lineage dysplasia and ineffective hematopoiesis. Despite identifying multiple gene mutations in patients with MDS, their main clinical features are similar. To resolve the discrepancy between genotypes and phenotypes, we performed transcriptome and epigenome analyses to ascertain the shared underlying mediator (s) of MDS etiology and identified HIF1A signaling as a central pathobiological mediator of MDS. HIF1A is a critical regulator for several physiological pathways associated with stem-cell maintenance, angiogenesis, glucose-metabolism, and immune activation. We identified dysregulated HIF1A signature in human patients with MDS. Using mouse genetic models, we demonstrated that the dysregulation of HIF1A could generate the clinically relevant diversity of MDS phenotypes by functioning as a signaling funnel for MDS-driver mutations. The genetic disruption of HIF1A resolves MDS phenotypes. These findings suggest that HIF1A is an effective therapeutic target for a broad spectrum of patients with MDS.


Assuntos
Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Síndromes Mielodisplásicas/genética , Animais , Hematopoese , Humanos , Camundongos , Mutação , Transdução de Sinais , Transcriptoma
12.
Adv Exp Med Biol ; 1143: 75-93, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31338816

RESUMO

As the most abundant internal modification in eukaryotic messenger RNAs (mRNAs), N 6-methyladenosine (m6A) modification has been shown recently to posttranscriptionally regulate expression of thousands of messenger RNA (mRNA) transcripts in each mammalian cell type in a dynamic and reversible manner. This epigenetic mark is deposited by the m6A methyltransferase complex (i.e., the METTL3/METTL14/WTAP complex and other cofactor proteins) and erased by m6A demethylases such as FTO and ALKBH5. Specific recognition of these m6A-modified mRNAs by m6A-binding proteins (i.e., m6A readers) determines the fate of target mRNAs through affecting splicing, nuclear export, RNA stability, and/or translation. During the past few years, m6A modification has been demonstrated to play a critical role in many major normal bioprocesses including self-renewal and differentiation of embryonic stem cells and hematopoietic stem cells, tissue development, circadian rhythm, heat shock or DNA damage response, and sex determination. Thus, it is not surprising that dysregulation of the m6A machinery is also closely associated with pathogenesis and drug response of both solid tumors and hematologic malignancies. In this chapter, we summarize and discuss recent findings regarding the biological functions and underlying mechanisms of m6A modification and the associated machinery in normal hematopoiesis and the initiation, progression, and drug response of acute myeloid leukemia (AML), a major subtype of leukemia usually associated with unfavorable prognosis.


Assuntos
Adenosina , Hematopoese , Leucemia Mieloide Aguda , Metiltransferases , RNA Mensageiro , Adenosina/metabolismo , Animais , Diferenciação Celular , Resistencia a Medicamentos Antineoplásicos/genética , Hematopoese/genética , Humanos , Leucemia Mieloide Aguda/fisiopatologia , Metiltransferases/metabolismo , RNA Mensageiro/metabolismo
13.
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
15.
Mol Carcinog ; 58(9): 1640-1647, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31264291

RESUMO

T-cell protein tyrosine phosphatase (TC-PTP, encoded by PTPN2) is a nonreceptor PTP that is most highly expressed in hematopoietic tissues. TC-PTP modulates a variety of physiological functions including cell cycle progression, cell survival and proliferation, and hematopoiesis through tyrosine dephosphorylation of its target substrates, such as EGFR, JAK1, JAK3, STAT1, and STAT3. Studies with whole or tissue-specific loss of TC-PTP function transgenic mice have shown that TC-PTP has crucial roles in the regulation of the immune response, insulin signaling, and oncogenic signaling. More recently, the generation of epidermal-specific TC-PTP-deficient mice for use in multistage skin carcinogenesis bioassays demonstrated that TC-PTP suppresses skin tumor formation by negatively regulating STAT3 and AKT signaling. Further investigation showed that TC-PTP also minimizes UVB-induced epidermal cell damage by promoting apoptosis through the negative regulation of Flk-1/JNK signaling. These findings provide major evidence for a tumor suppressive function for TC-PTP against environment-induced skin cancer. Here, we will discuss TC-PTP, its substrates, and its functions with an emphasis on its role in skin carcinogenesis.


Assuntos
Carcinogênese/metabolismo , Células Epiteliais/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 2/metabolismo , Animais , Ciclo Celular/fisiologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Epiderme/metabolismo , Epiderme/fisiologia , Células Epiteliais/fisiologia , Hematopoese/fisiologia , Humanos , Transdução de Sinais/fisiologia
16.
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
17.
Immunity ; 51(1): 3-5, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315035

RESUMO

Little is known about the inflammasome beyond its function in innate immune response. In this issue of Immunity, Tyrkalska et al. report that the inflammasome regulates the balance between erythroid and myeloid differentiation in model systems, providing insights into hematopoietic lineage bias associated with inflammatory conditions.


Assuntos
Fator de Transcrição GATA1 , Inflamassomos , Hematopoese , Imunidade Inata , Proteína 3 que Contém Domínio de Pirina da Família NLR
18.
Rinsho Ketsueki ; 60(5): 417-422, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31168007

RESUMO

Acquired aplastic anemia (AA) is a hematopoietic disorder caused by an immunologic attack on hematopoietic stem cells (HSCs). The presence of cells with a paroxysmal nocturnal hemoglobinuria (PNH) phenotype or with copy-number neutral loss of heterozygosity of chromosome 6p (6pLOH) suggests an immune-mediated pathophysiology underlying AA. Recently, genomic studies have revealed clonal hematopoiesis by HSCs with altered genes. PIGA, DNMT3A, ASXL1, BCOR, 6pLOH, and HLA class I allele mutations are common in patients with AA. The genomic landscape of AA is distinct from that of the myelodysplastic syndrome or age-related clonal hematopoiesis. This suggests that escape from an autoimmune attack is strongly associated with clonal hematopoiesis in AA. Eltrombopag (EPAG), a thrombopoietin receptor agonist, has recently emerged as a novel therapeutic agent for AA. Further studies are needed to clarify whether EPAG induces clonal expansion of these clones.


Assuntos
Anemia Aplástica/diagnóstico , Anemia Aplástica/terapia , Hematopoese , Células-Tronco Hematopoéticas , Hemoglobinúria Paroxística , Humanos , Síndromes Mielodisplásicas
19.
Int J Infect Dis ; 85: 114-116, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31170547

RESUMO

We report the first case of pulmonary scedosporiosis detected by next-generation sequencing (NGS) from bronchoalveolar lavage fluid (BALF) in a 67-year-old male with bronchiectasis and hematopoietic failure. Scedosporium apiospermum is a ubiquitous organism present in the environment with intrinsic resistance to many antifungal agents. The patient developed respiratory failure, pulmonary consolidation, and septic shock shortly thereafter, and responded poorly to antifungal therapy. This case highlights the combined application of NGS and traditional fungal culture in the clinical diagnosis of pulmonary invasive fungal disease. NGS is proposed as an important adjunctive diagnostic approach for uncommon pathogens.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Infecções Fúngicas Invasivas/diagnóstico , Pneumopatias Fúngicas/diagnóstico , Scedosporium , Idoso , Líquido da Lavagem Broncoalveolar/microbiologia , Hematopoese , Humanos , Infecções Fúngicas Invasivas/complicações , Pneumopatias Fúngicas/complicações , Masculino , Insuficiência Respiratória/etiologia , Choque Séptico/etiologia
20.
Nat Commun ; 10(1): 2891, 2019 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-31253791

RESUMO

Our ability to manage acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption central to leukemogenesis, including improper histone methylation. Here we examine 16 histone H3 genes in 434 primary AML samples and identify Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), with higher incidence in secondary AML (9%). These mutations occur in pre-leukemic hematopoietic stem cells (HSCs) and exist in the major leukemic clones in patients. They increase the frequency of functional HSCs, alter differentiation, and amplify leukemic aggressiveness. These effects are dependent on the specific mutation. H3K27 mutation increases the expression of genes involved in erythrocyte and myeloid differentiation with altered H3K27 tri-methylation and K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutation, although they at times co-occur. This study establishes that H3 mutations are drivers of human pre-cancerous stem cell expansion and important early events in leukemogenesis.


Assuntos
Epigenômica , Regulação Leucêmica da Expressão Gênica/fisiologia , Histonas/metabolismo , Leucemia Mieloide Aguda/metabolismo , Animais , Animais Geneticamente Modificados , Antineoplásicos/farmacologia , Sequência de Bases , Células da Medula Óssea , Diferenciação Celular , Transformação Celular Neoplásica , DNA/genética , Drosophila melanogaster/genética , Regulação Leucêmica da Expressão Gênica/efeitos dos fármacos , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Mutação , Neoplasias Experimentais
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