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1.
Sci Rep ; 8(1): 11303, 2018 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-30038350

RESUMO

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

2.
Sci Rep ; 8(1): 7210, 2018 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-29740078

RESUMO

Chromatin structure is a major regulator of transcription and gene expression. Herein we explore the use of osmotic modulation to modify the chromatin structure and reprogram gene expression. In this study we use the extracellular osmotic pressure as a chromatin structure and transcriptional modulator. Hyposmotic modulation promotes chromatin loosening and induces changes in RNA polymerase II (Pol II) activity. The chromatin decondensation opens space for higher amounts of DNA engaged RNA Pol II. Hyposmotic modulation constitutes an alternative route to manipulate cell fate decisions. This technology was tested in model protocols of induced pluripotency and transdifferentiation in cells growing in suspension and adherent to substrates, CD34+ umbilical-cord-blood (UCB), fibroblasts and B-cells. The efficiency and kinetics of these cell fate modulation processes were improved by transient hyposmotic modulation of the cell environment.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Transdiferenciação Celular/efeitos dos fármacos , Cromatina/química , Meios de Cultura/farmacologia , Pressão Osmótica , Células-Tronco/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Linfócitos B/ultraestrutura , Células Cultivadas , Cromatina/ultraestrutura , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Meios de Cultura/química , DNA/genética , DNA/metabolismo , Sangue Fetal , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/ultraestrutura , Humanos , Células K562 , Cinética , Osmose , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Células-Tronco/metabolismo , Células-Tronco/ultraestrutura , Transcrição Genética/efeitos dos fármacos
3.
Leukemia ; 31(5): 1079-1086, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-27807368

RESUMO

The origin of cancers is associated with etiology as well as therapeutics. Several studies reveal that malignancies in children can originate in utero. However, a diagnostic approach to distinguish between cancers initiated pre- or postnatally is absent. Here we identified a transcriptional factor FEV (fifth Ewing variant) that was expressed in fetal hematopoietic cells and became silent after birth. We characterized that FEV was essential for the self-renewal of hematopoietic stem cells (HSCs). We next found that FEV was expressed in most infant leukemia samples, but seldom in adult samples, in accord with the known prenatal origins of the former. We further determined the majority of pediatric acute lymphoid leukemia (ALL) and acute myeloid leukemia (AML) were FEV positive. Moreover, FEV knockdown markedly impaired the leukemia-propagating ability of leukemic stem cells. We therefore identified FEV is unique to fetal HSCs and stably expressed in leukemic cells of prenatal origin. It may also provide a tractable therapeutic target.


Assuntos
Proteínas de Ligação a DNA/análise , Doenças Fetais/diagnóstico , Células-Tronco Hematopoéticas/metabolismo , Leucemia/etiologia , Proteínas Nucleares/análise , Animais , Células Cultivadas , Proteínas de Ligação a DNA/biossíntese , Feminino , Doenças Fetais/metabolismo , Expressão Gênica , Xenoenxertos , Humanos , Leucemia/diagnóstico , Leucemia/metabolismo , Leucemia Mieloide Aguda , Camundongos , Proteínas Nucleares/biossíntese , Leucemia-Linfoma Linfoblástico de Células Precursoras , Gravidez , Fatores de Transcrição
4.
Oncogene ; 34(16): 2083-93, 2015 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-24909160

RESUMO

Leukemic lymphoblasts within different immunophenotypic populations possess stem cell properties. However, whether or not the self-renewal program is retained from stem cells or conferred on progenitors by leukemogenic molecules remains unknown. We have addressed the issue in the context of TEL-AML1-associated acute lymphoblastic leukemia (ALL) by profiling a refined program edited from genes essential for self-renewal of hematopoietic stem cells and B-cell development. Bioinformatic analysis shows that ALL populations are loosely clustered and close to the normal population that contains stem and primitive progenitor cells. This finding indicates that immunophenotypes do not reflect maturation stages in ALL and that the self-renewal program may be retained from stem cells. Results of assessing 'first hit' function of TEL-AML1 in different populations of normal cells demonstrate the molecular model. Therefore, the current study shows a leukemogenic scenario of human ALL in which programs of stem cells are sustained in distinct fractions by leukemogenic mutations.


Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/genética , Células-Tronco Hematopoéticas/patologia , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , ADP-Ribosil Ciclase 1/biossíntese , Adolescente , Antígenos CD19/biossíntese , Antígenos CD34/biossíntese , Linfócitos B/patologia , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Hematopoese/genética , Humanos , Lactente , Masculino , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética
5.
Plast Surg Int ; 2013: 129692, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23509622

RESUMO

Objective. The objective of this study is to determine the incidence of PUs, the distribution of PUs, common injuries contributing to the occurrence of PUs in patients admitted to the Department of Plastic and Reconstructive Surgery Kosovo for surgical interventions of PUs, localization of PUs in body, the topical treatment of pressure ulcers before surgical intervention, the methods of surgical interventions, number of surgical interventions, duration of treatment, complications, and mortality. Materials and Methods. This study includes 55 patients with PUs treated surgically in 2000-2010 period in the Department of Plastic and Reconstructive Surgery Kosovo. The data were collected and analyzed from the archives and protocols of the University Clinical Center of Kosovo. Data processing was done with the statistical package In Stat 3. From statistical parameters arithmetic median and standard deviation were calculated. Data testing is done with χ (2)-test and the difference is significant if P < 0.05. Conclusion. Despite preventive measures against PUs, the incidence of Pus remains high.

7.
Oncogene ; 26(47): 6750-65, 2007 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-17934483

RESUMO

An increasing number of molecules have been identified as candidate regulators of stem cell fates through their involvement in leukaemia or via post-genomic gene discovery approaches. A full understanding of the function of these molecules requires (1) detailed knowledge of the gene networks in which they participate and (2) an appreciation of how these networks vary as cells progress through the haematopoietic cell hierarchy. An additional layer of complexity is added by the occurrence of different haematopoietic cell hierarchies at different stages of ontogeny. Beyond these issues of cell context dependence, it is important from a mechanistic point of view to define the particular cell fate pathway impacted by any given regulator. Herein, we advance the notion that haematopoietic stem cells (HSC), which sustain haematopoiesis throughout adult life and are specified in foetal life, have a minimal or late contribution to foetal haematopoiesis but instead largely proliferate during the foetal period. In light of this notion, we revisit published data on mouse knockouts of haematopoietically-affiliated transcription factors highlighting novel insights that may be gained from taking such a view.


Assuntos
Feto/fisiologia , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/fisiologia , Fatores de Transcrição/fisiologia , Transcrição Genética/fisiologia , Animais , Feto/metabolismo , Hematopoese/genética , Células-Tronco Hematopoéticas/metabolismo , Humanos
11.
Leukemia ; 18(3): 375-84, 2004 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-14737069

RESUMO

A fundamental issue in cancer biology is the identification of the target cell in which the causative molecular lesion arises. Acute myeloid leukemia (AML) is thought to reflect the transformation of a primitive stem cell compartment. The resultant 'cancer stem cells' comprise only a minor portion of the leukemic clone but give rise through differentiation to more committed progenitors as well as differentiated blasts that constitute the bulk of the tumor. The maintenance of the leukemic clone is dependent on the self-renewal capacity of the cancer stem cell compartment, which is revealed by its ability to re-initiate leukemia in a transplant setting. The cellular basis of acute promyelocytic leukemia (APL) is however less clear. APL has traditionally been considered to be the most differentiated form of AML and to arise from a committed myeloid progenitor. Here we review apparently conflicting evidence pertaining to the cellular origins of APL and propose that this leukemia may originate in more than one cellular compartment. This view could account for many apparent inconsistencies in the literature to date. An understanding of the nature of the target cell involved in transformation of APL has important implications for biological mechanism and for clinical treatment.


Assuntos
Células-Tronco Hematopoéticas/patologia , Leucemia Mieloide/patologia , Leucemia Promielocítica Aguda/patologia , Doença Aguda , Diferenciação Celular , Linhagem da Célula , Humanos
12.
Blood ; 98(8): 2563-7, 2001 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-11588055

RESUMO

To better understand the role of retinoids in myelopoiesis, expression of the retinoid receptor genes (retinoic acid receptors [RARs] and retinoid X receptors [RXRs]) were examined during differentiation of factor-dependent cell-Paterson (FDCP)-mixA4 murine progenitor cells. The major receptor expressed in undifferentiated A4 cells was RARalpha (primarily the RARalpha1 isoform). Following induction of myelomonocytic differentiation with granulocyte and granulocyte-macrophage colony-stimulating factors, a dramatic increase in RARalpha expression (particularly the RARalpha2 isoform) was seen. In contrast, expression of both RARalpha isoforms was rapidly extinguished upon induction of erythroid differentiation with erythropoeitin (EPO). A modest induction of RXRalpha expression was seen, particularly during differentiation in the myelomonocytic lineage. Low expression levels of RARgamma2 and RXRbeta remained unchanged, irrespective of differentiation pathway. Consistent with the gene expression patterns, RARalpha agonists and antagonists stimulated myelomonocytic and erythroid differentiation of FDCP-mixA4 cells, respectively. Taken together, these results suggest that erythropoiesis and granulopoiesis require diminished and enhanced RARalpha activities, respectively, which at physiological all-trans-retinoic acid (RA) concentrations may be accomplished by reciprocal effects of EPO and myelomonocytic growth factors on its expression. This hypothesis is corroborated by data showing that RA, which positively regulates RARalpha2 expression, can exert inhibitory effects on erythroid differentiation.


Assuntos
Diferenciação Celular/fisiologia , Regulação da Expressão Gênica , Receptores do Ácido Retinoico/genética , Medula Óssea/fisiologia , Células da Medula Óssea/citologia , Diferenciação Celular/genética , Células Cultivadas , Primers do DNA , Eritropoetina/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Fator Estimulador de Colônias de Granulócitos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Células HL-60 , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/fisiologia , Humanos , Leucemia , Modelos Biológicos , Receptores do Ácido Retinoico/efeitos dos fármacos , Receptor alfa de Ácido Retinoico , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tretinoína/farmacologia , Células Tumorais Cultivadas
13.
Mol Cell Biol ; 20(17): 6276-86, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-10938104

RESUMO

The hematopoietically expressed GATA family of transcription factors function as key regulators of blood cell fate. Among these, GATA-2 is implicated in the survival and growth of multipotential progenitors. Here we report that the promyelocytic leukemia protein (PML) can complex with GATA-2 and potentiate its transactivation capacity. The binding is mediated through interaction of the zinc finger region of GATA-2 and the B-box domain of PML. The B-box region of PML is retained in the PML-RARalpha (retinoic acid receptor alpha) fusion protein generated by the t(15;17) translocation characteristic of acute promyelocytic leukemia (APL). Consistent with this, we provide evidence that GATA-2 can physically associate with PML-RARalpha. Functional experiments further demonstrated that this interaction has the capacity to render GATA-dependent transcription inducible by retinoic acid, raising the possibility that GATA target genes may be involved in the molecular pathogenesis of APL.


Assuntos
Cromossomos Humanos Par 15 , Cromossomos Humanos Par 17 , Proteínas de Ligação a DNA/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas Nucleares , Proteínas de Fusão Oncogênica , Receptores do Ácido Retinoico/metabolismo , Fatores de Transcrição/metabolismo , Translocação Genética , Animais , Células COS , Linhagem Celular , Núcleo Celular/metabolismo , DNA/metabolismo , Proteínas de Ligação a DNA/química , Fator de Transcrição GATA2 , Humanos , Leucemia Promielocítica Aguda/metabolismo , Camundongos , Proteínas de Neoplasias/química , Plasmídeos/metabolismo , Testes de Precipitina , Proteína da Leucemia Promielocítica , Ligação Proteica , Estrutura Terciária de Proteína , Receptor alfa de Ácido Retinoico , Fatores de Transcrição/química , Ativação Transcricional , Tretinoína/farmacologia , Células Tumorais Cultivadas , Proteínas Supressoras de Tumor , Técnicas do Sistema de Duplo-Híbrido
14.
Curr Biol ; 9(24): R933-5, 1999.
Artigo em Inglês | MEDLINE | ID: mdl-10607584

RESUMO

Recent studies have identified the transcription factor Pax5 as a critical determinant of commitment to the B-lymphocyte pathway. Surprisingly, Pax5 appears to achieve this primarily through suppressing alternative haematopoietic lineage fates.


Assuntos
Linfócitos B/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas Nucleares/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linfócitos B/citologia , Diferenciação Celular , Proteínas de Ligação a DNA/genética , Hematopoese , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Camundongos , Camundongos Knockout , Proteínas Nucleares/genética , Fator de Transcrição PAX5 , Fatores de Transcrição/genética
15.
Blood ; 94(5): 1495-503, 1999 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-10477673

RESUMO

Herein, we show that CD34, c-kit double-positive (CD34(+)c-kit(+)) cells from the aorta-gonad-mesonephros (AGM) region of the developing mouse are multipotent in vitro and can undergo both B-lymphoid and multimyeloid differentiation. Molecular analysis of individual CD34(+)c-kit(+) cells by single-cell reverse transcriptase-polymerase chain reaction (RT-PCR) shows coactivation of erythroid (beta-globin) and myeloid (myeloperoxidase [MPO]) but not lymphoid-affiliated (CD3, Thy-1, and lambda5) genes. Additionally, most cells coexpress the stem cell-associated transcriptional regulators AML-1, PU.1, GATA-2 and Lmo2, as well as the granulocyte colony-stimulating factor receptor (G-CSF-R). These results show that the CD34(+)c-kit(+) population from the AGM represents a highly enriched source of multipotent hematopoietic cells, and suggest that limited coactivation of distinct lineage-affiliated genes is an early event in the generation of hematopoietic stem and progenitor cells during ontogeny.


Assuntos
Eritropoese , Feto/citologia , Células-Tronco Hematopoéticas/citologia , Leucopoese , Animais , Antígenos CD34 , Aorta/citologia , Aorta/embriologia , Aorta/fisiologia , Diferenciação Celular , Eritropoese/genética , Feto/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Gônadas/citologia , Gônadas/embriologia , Gônadas/fisiologia , Células-Tronco Hematopoéticas/fisiologia , Leucopoese/genética , Mesonefro/citologia , Mesonefro/embriologia , Mesonefro/fisiologia , Camundongos , Proteínas Proto-Oncogênicas c-kit
16.
Genes Dev ; 13(14): 1847-60, 1999 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-10421636

RESUMO

The transcription factor GATA-2 is expressed in hematopoietic stem and progenitor cells and is functionally implicated in their survival and proliferation. We have used estrogen and tamoxifen-inducible forms of GATA-2 to modulate the levels of GATA-2 in the IL-3-dependent multipotential hematopoietic progenitor cell model FDCP mix. Ligand-dependent induction of exogenous GATA-2 activity did not rescue cells deprived of IL-3 from apoptosis. However, induction of GATA-2 activity in cells cultured in IL-3 blocked factor-dependent self-renewal but not factor-dependent survival: Cells undergo cell cycle arrest and cease proliferating but do not apoptose. This was accompanied by differentiation down the monocytic and granulocytic pathways. Differentiation occurred in the presence of IL-3 and did not require addition of exogenous differentiation growth factors such as G-CSF or GM-CSF normally required to induce granulomonocytic differentiation of FDCP-mix cells. Conversely, EPO-dependent erythroid differentiation was inhibited by GATA-2 activation. These biological effects were obtained with levels of exogenous GATA-2 representing less than twofold increases over endogenous GATA-2 levels and were not observed in cells overexpressing GATA-1/ER. Similar effects on proliferation and differentiation were also observed in primary progenitor cells, freshly isolated from murine bone marrow and transduced with a GATA-2/ER-containing retrovirus. Taken together, these data suggest that threshold activities of GATA-2 in hematopoietic progenitor cells are a critical determinant in influencing self-renewal versus differentiation outcomes.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Receptores Estrogênicos/metabolismo , Fatores de Transcrição/metabolismo , Animais , Sequência de Bases , Diferenciação Celular/genética , Linhagem Celular , Linhagem da Célula , Primers do DNA , Proteínas de Ligação a DNA/genética , Fatores de Ligação de DNA Eritroide Específicos , Fator de Transcrição GATA1 , Fator de Transcrição GATA2 , Regulação da Expressão Gênica no Desenvolvimento , Ligantes , Camundongos , Receptores Estrogênicos/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Fatores de Transcrição/genética
17.
Leukemia ; 12(11): 1771-81, 1998 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-9823953

RESUMO

Through differential screening of established human leukaemia cell lines, we have identified and molecularly cloned lymphopain, a novel cysteine proteinase of the papain family. Lymphopain exhibits a remarkably restricted cellular pattern of expression, being predominantly expressed in cytotoxic T-lymphocytes and natural killer cells. The human lymphopain locus maps to chromosome 11q13, encodes a polypeptide of 376 amino acids and is conserved in the mouse. Both human and murine forms appear more closely related to protozoan papain-like enzymes than to other mammalian members of the papain family. The cellular distribution of lymphopain expression, together with the functional demonstration of lymphopain-associated proteinase activity in vitro, is suggestive of a role for lymphopain in immune cell-mediated, cell killing.


Assuntos
Cisteína Endopeptidases/metabolismo , Células Matadoras Naturais/enzimologia , Leucemia Linfoide/enzimologia , Linfócitos T Citotóxicos/enzimologia , Sequência de Aminoácidos , Animais , Sequência de Bases , Catepsina W , Mapeamento Cromossômico , Cromossomos Humanos Par 11 , Clonagem Molecular , Sequência Conservada , Cisteína Endopeptidases/genética , DNA Complementar , Evolução Molecular , Humanos , Imunofenotipagem , Leucemia Linfoide/imunologia , Camundongos , Dados de Sequência Molecular , Homologia de Sequência de Aminoácidos
18.
Mol Cell ; 2(4): 447-55, 1998 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-9809066

RESUMO

The murine beta-globin locus control region (LCR) was deleted from its native chromosomal location. The approximately 25 kb deletion eliminates all sequences and structures homologous to those defined as the human LCR. In differentiated ES cells and erythroleukemia cells containing the LCR-deleted chromosome, DNasel sensitivity of the beta-globin domain is established and maintained, developmental regulation of the locus is intact, and beta-like globin RNA levels are reduced 5%-25% of normal. Thus, in the native murine beta-globin locus, the LCR is necessary for normal levels of transcription, but other elements are sufficient to establish the open chromatin structure, transcription, and developmental specificity of the locus. These findings suggest a contributory rather than dominant function for the LCR in its native location.


Assuntos
Cromatina/fisiologia , Globinas/genética , Ativação Transcricional/fisiologia , Animais , Desoxirribonucleases , Deleção de Genes , Expressão Gênica/fisiologia , Globinas/química , Humanos , Leucemia Eritroblástica Aguda , Camundongos , Fenótipo , Conformação Proteica , Estrutura Terciária de Proteína , Células Tumorais Cultivadas/química , Células Tumorais Cultivadas/fisiologia
19.
Blood ; 92(5): 1505-11, 1998 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-9716576

RESUMO

The Notch signaling system regulates proliferation and differentiation in many tissues. Notch is a transmembrane receptor activated by ligands expressed on adjacent cells. Hematopoietic stem cells and early progenitors express Notch, making the stromal cells which form cell-cell contacts with progenitor cells candidate ligand-presenting cells in the hematopoietic microenvironment. Therefore, we examined primary stromal cell cultures for expression of Notch ligands. Using reverse transcription-polymerase chain reaction, in situ hybridization, immunohistochemistry, and Western blotting, we demonstrate expression of Jagged 1 in primary stromal cultures. To investigate if the stromal expression of Jagged 1 has functional effects on hematopoietic progenitors, we cultured CD34(+), c-kit+ hematopoietic progenitor cells derived from the aorto gonadal mesonephros region of day 11 mouse embryos on the Jagged 1(-) stromal cell line S17 and on S17 cells engineered to express Jagged 1. The presence of Jagged 1 increased the number of colonies formed in subsequent methylcellulose culture fourfold. Larger increases in colony numbers were observed under the same culture conditions with CD34(+), c-kit+ hematopoietic progenitor cells derived from d11 fetal liver. These results obtained in vitro table Jagged 1 as a candidate regulator of stem cell fate in the context of stromal microenvironments in vivo.


Assuntos
Expressão Gênica , Células-Tronco Hematopoéticas/citologia , Proteínas de Membrana/genética , Células Estromais/metabolismo , Animais , Antígenos CD34/análise , Aorta/citologia , Aorta/embriologia , Western Blotting , Proteínas de Ligação ao Cálcio , Células Cultivadas , Embrião de Mamíferos , Gônadas/citologia , Gônadas/embriologia , Células-Tronco Hematopoéticas/imunologia , Imuno-Histoquímica , Hibridização In Situ , Peptídeos e Proteínas de Sinalização Intercelular , Proteína Jagged-1 , Mesonefro/citologia , Mesonefro/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos CBA , Reação em Cadeia da Polimerase , Proteínas Proto-Oncogênicas c-kit/análise , DNA Polimerase Dirigida por RNA , Proteínas Serrate-Jagged
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