RESUMO
BACKGROUND: MicroRNA (miRNA, miR)-18a is a member of the miR-17-92 cluster, an important locus that is markedly overexpressed in several cancers and associated with cancer development and progression. However, the mechanism of action of the miR-17-92 cluster and its individual miRNAs are largely unknown. METHODS AND RESULTS: In this study, we investigated the expression of the miR-17-92 cluster by in situ hybridisation (ISH) assay and copy-number analysis in gastric tissue microarray (TMA) specimens. We determined that miR-18a was present at higher levels than the other five miRNAs in the cluster. In addition, we identified Protein Inhibitor of Activated Signal Transducer and Activator of Transcription 3 (PIAS3) as a direct target of miR-18a in gastric cancer. miR-18a level was positively correlated with levels of Survivin, Bcl-xL, and c-Myc, which are downstream transcriptional targets of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3-induced transcription can be negatively regulated by PIAS3; consistent with this, PIAS3 level was negatively correlated with levels of Survivin, Bcl-xL, and c-Myc. CONCLUSION: Our findings indicate that miR-18a acts as an oncogene and plays a role in gastric adenocarcinogenesis, at least in part by negatively regulating PIAS3 and thereby modulating expression of STAT3 target genes.
Assuntos
Adenocarcinoma/genética , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Chaperonas Moleculares/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Fator de Transcrição STAT3/metabolismo , Neoplasias Gástricas/genética , Adenocarcinoma/metabolismo , Adenocarcinoma/patologia , Idoso , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Proliferação de Células , Feminino , Mucosa Gástrica/metabolismo , Humanos , Técnicas Imunoenzimáticas , Hibridização In Situ , Masculino , Chaperonas Moleculares/genética , Estadiamento de Neoplasias , Prognóstico , Proteínas Inibidoras de STAT Ativados/genética , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT3/genética , Estômago/patologia , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Análise Serial de Tecidos , Células Tumorais CultivadasRESUMO
In 2007, the Japanese Red Cross Blood Center performed a large-scale questionnaire study of post-donation adverse reactions. The questionnaire was distributed to 98,389 donors, and the answers were returned by 55,231 (56.1%). In total, 2,877 (5.2%) complained of an adverse reaction. Assuming that there were no adverse reactions for the 46,150 donors who did not reply, the rate of adverse reaction can be speculated to be 2.8%. Our study strongly suggests that blood centers have long underestimated the risks of vaso-vagal reactions. Taking at least 6h of careful rest after donation would be a helpful counter measure.
Assuntos
Doadores de Sangue/estatística & dados numéricos , Inquéritos e Questionários/normas , Síncope Vasovagal/etiologia , Adulto , Humanos , Japão , Masculino , Fatores de RiscoRESUMO
BACKGROUND: Translocated in liposarcoma-CCAAT/enhancer binding protein homologous protein (TLS-CHOP) (also known as FUS-DDIT3) chimeric oncoprotein is found in the majority of human myxoid liposarcoma (MLS), but its molecular function remains unclear. METHODS: We knockdowned TLS-CHOP expression in MLS-derived cell lines by a specific small interfering RNA, and analysed the gene expression profiles with microarray. RESULTS: TLS-CHOP knockdown inhibited growth of MLS cells, and induced an anticancer cytokine, melanoma differentiation-associated gene 7 (MDA-7)/interleukin-24 (IL-24) expression. However, double knockdown of TLS-CHOP and MDA-7/IL-24 did not inhibit MLS cell growth. CONCLUSION: Repression of MDA-7/IL-24 expression by TLS-CHOP is required for MLS tumour growth, and TLS-CHOP may become a promising therapeutic target for MLS treatment.
Assuntos
Interleucinas/metabolismo , Lipossarcoma Mixoide/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Proteína FUS de Ligação a RNA/metabolismo , Fator de Transcrição CHOP/metabolismo , Expressão Gênica , Perfilação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Interleucinas/genética , Lipossarcoma Mixoide/genética , Proteínas de Fusão Oncogênica/genética , Proteína FUS de Ligação a RNA/genética , Fator de Transcrição CHOP/genéticaRESUMO
Recent advances of biotechnology have laid the groundwork for potent and specific molecular-targeting therapies including RNA interference. The largest remaining hurdle for widespread use of this technology in skin is an effective delivery system. Here, we demonstrate an effective topical delivery system using a cream formulation containing a small-interfering RNA (siRNA) that specifically targets osteopontin (OPN). OPN is a validated target in numerous inflammatory diseases, including rheumatoid arthritis (RA). The siRNA targeting OPN was incorporated into a cream formulation GeneCream that penetrates the stratum corneum, depositing siRNA in the epidermis, dermis, and to a lesser extent, subcutaneous tissue. In addition, when the OPN siRNA cream was topically applied to the skin of a collagen antibody-induced RA mouse model, the siRNA cream prevented the occurrence of severe, irreversible damage to bone and cartilage. Thus, the siRNA cream provides effective delivery of active OPN siRNA, suggesting this formulation may represent a platform technology for delivery of siRNAs for treating various disorders including RA.
Assuntos
Artrite Experimental/terapia , Terapia Genética/métodos , Osteopontina/genética , Interferência de RNA , Administração Tópica , Animais , Artrite Reumatoide/terapia , Feminino , Regulação da Expressão Gênica , Marcação de Genes/métodos , Técnicas de Transferência de Genes , Camundongos , Camundongos Endogâmicos BALB C , Pomadas/efeitos adversos , Osteopontina/metabolismo , RNA Interferente Pequeno/administração & dosagem , Pele , Absorção CutâneaRESUMO
G-protein-coupled receptor kinases (GRKs) comprise a family of seven mammalian serine/threonine protein kinases that phosphorylate and regulate agonist-bound, activated, G-protein-coupled receptors (GPCRs). GRKs and beta-arrestins are key participants in the canonical pathways leading to phosphorylation-dependent GPCR desensitization, endocytosis, intracellular trafficking and resensitization. Here we show that GRK4 isoforms are expressed in human breast cancer but not in normal epithelia. In addition, GRK4-over-expressing cells activated the mitogen-activated protein kinase (MAPK) mediated by ERK 1/2 and JNK phosphorylation in breast cancer-derived cell lines. Furthermore, suppression of beta-arrestins decreased GRK4-stimulated ERK 1/2 or JNK phosphorylations. These data indicate that high-level expression of GRK4 may activate MAPK signalling pathways mediated by beta-arrestins in breast cancer cells, suggesting that GRK4 may be implicated in breast cancer carcinogenesis.
Assuntos
Neoplasias da Mama/genética , Quinase 4 de Receptor Acoplado a Proteína G/genética , Isoformas de Proteínas/genética , Arrestinas/análise , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Ativação Enzimática , Feminino , Quinase 4 de Receptor Acoplado a Proteína G/análise , Expressão Gênica , Humanos , Immunoblotting/métodos , Imuno-Histoquímica , MAP Quinase Quinase 4/metabolismo , Sistema de Sinalização das MAP Quinases , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosforilação , Isoformas de Proteínas/análise , Interferência de RNA , RNA Interferente Pequeno/farmacologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , beta-ArrestinasRESUMO
We analysed 86 patients with CML who received unrelated cord blood transplantation (UCBT), identified through a registry of the Japan Cord Blood Bank Network. At transplantation, the median patient age was 39 years (range, 1-67 years); 38 patients were in chronic phase (CP), 13 in the accelerated phase (AP) and 35 in blast crisis (BC). Median duration from diagnosis to UCBT was 1.5 years (range, 0.2-14.6 years). A nucleated cell (NC) dose of more than 3.0 x 10(7) per kg was sufficient to achieve neutrophil (91%) and platelet recovery (86%), whereas the lower dose of NC achieved only 60 and 61%, respectively. The duration and type of pre-transplant treatment did not affect neutrophil or platelet recovery. Results of multivariate analysis indicated that older patients (>50 years) had a higher incidence of transplant-related mortality. Advanced-disease stage and lower doses of NCs were significantly associated with lower leukaemia-free and event-free survival. At 2-year survival for patients in CP, AP and BC was 71, 59 and 32%, respectively (P=0.0004). A pre-transplant European Group for Blood and Marrow Transplantation scoring system was effective in predicting the outcome of UCBT. We conclude that UCBT is a reasonable alternative therapy for patients with CML.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Leucemia Mielogênica Crônica BCR-ABL Positiva/terapia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de RiscoAssuntos
Terapia Baseada em Transplante de Células e Tecidos/instrumentação , Terapia Baseada em Transplante de Células e Tecidos/métodos , Terapia Baseada em Transplante de Células e Tecidos/normas , Seleção do Doador , Bancos de Sangue , Doadores de Sangue , Segurança do Sangue , Transfusão de Sangue , Humanos , Cooperação Internacional , Segurança do Paciente , Controle de Qualidade , Inquéritos e Questionários , Doadores de TecidosRESUMO
Although it is known that human leukocyte antigen (HLA)-DPB1 disparity has a strong impact on outcomes in unrelated hematopoietic transplantation with induction of acute graft-versus-host disease (GVHD) and a graft-versus-leukemia (GVL) effect, its role in unrelated umbilical cord blood transplantation (UR-CBT) has yet to be fully clarified. Our current study is being conducted to elucidate the impact of HLA-DPB1 mismatch, along with the effect of other HLA loci mismatches at the allele level. HLA six loci alleles were retrospectively typed in 1157 Japanese donors and patients with leukemia or myelodysplastic syndrome who underwent transplantation with a single unit of cord blood. HLA-DPB1 mismatch was associated with a significant reduction in leukemia relapse (hazard ratio 0.61, P<0.001), whereas the other HLA loci allele-level mismatches did not. No significant effect of HLA-DPB1 mismatch was observed in the risk of acute GVHD, engraftment or mortality. This HLA-DPB1 GVL effect without induction of severe acute GVHD or deterioration of survival rate has not been reported in unrelated bone marrow or peripheral blood stem cell transplantations, suggesting apparent advantages of UR-CBT. Accordingly, selection of an HLA-DPB1 mismatch cord blood might be the preferable choice for single-unit UR-CBT.
Assuntos
Doença Enxerto-Hospedeiro/imunologia , Efeito Enxerto vs Leucemia/imunologia , Cadeias beta de HLA-DP/imunologia , Leucemia/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Transplante de Medula Óssea/métodos , Criança , Pré-Escolar , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Síndromes Mielodisplásicas/imunologia , Transplante de Células-Tronco de Sangue Periférico/métodos , Transplante Homólogo/métodos , Doadores não Relacionados , Adulto JovemRESUMO
In order to examine GvHD prophylaxis in umbilical cord blood transplantation (UCBT) in more detail, we compared transplant outcomes after UCBT for acute leukemia among GvHD prophylaxes using registry data. We selected patients transplanted with a calcineurin inhibitor and methotrexate (MTX)/mycophenolate mofetil (MMF) combination. A total of 1516 first myeloablative UCBT between 2000 and 2012 (Cyclosporine A (CyA) plus MTX, 824, Tacrolimus (Tac) plus MTX, 554, Tac plus MMF, 138) were included. With adjusted analyses, Tac plus MMF showed a significantly higher risk for grade II-IV and III-IV acute GvHD than CyA or Tac plus MTX. Although NRM was similar, Tac plus MMF showed a significantly lower risk of relapse than CyA or Tac plus MTX. A significant difference was observed in the risk of overall mortality (OM) between the MTX-containing group and MMF-containing group. In patients with standard-risk disease, there was no significant difference in the risk of OM in any GvHD prophylaxis. However, in patients with advanced-risk disease, Tac plus MMF showed a significantly lower risk of OM. Therefore, MTX-containing prophylaxis is preferred in UCBT for standard-risk disease, whereas MMF-containing prophylaxis is preferred for advanced-risk disease. A prospective study to identify optimal GvHD prophylaxis for UCBT is warranted.
Assuntos
Transplante de Células-Tronco de Sangue do Cordão Umbilical , Doença Enxerto-Hospedeiro/mortalidade , Doença Enxerto-Hospedeiro/prevenção & controle , Metotrexato/administração & dosagem , Ácido Micofenólico/administração & dosagem , Adolescente , Adulto , Ciclosporina/administração & dosagem , Intervalo Livre de Doença , Feminino , Humanos , Incidência , Japão , Leucemia Mieloide Aguda/mortalidade , Leucemia Mieloide Aguda/terapia , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Sistema de Registros , Taxa de Sobrevida , Tacrolimo/administração & dosagemAssuntos
Criopreservação/métodos , Criopreservação/normas , Células-Tronco Hematopoéticas/citologia , Gestão da Qualidade Total/métodos , Gestão da Qualidade Total/normas , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Masculino , Controle de Qualidade , Transplante HomólogoRESUMO
Human erythrocyte ghosts were oxidized with tert-butyl hydroperoxide and subsequently treated with tritiated borohydride to label the membrane proteins modified during the membrane oxidation. From the ghosts, oxidized-and-tritiated glycophorin A was isolated and characterized. No intermolecular cross-links were observed as analyzed by sodium dodecylsulfate gel electrophoresis. But, the number of lysine residues was significantly reduced and susceptibility to proteinases such as trypsin, chymotrypsin and pronase was lower than that of control glycophorin A. Trypsinization of the oxidized-and-tritiated glycophorin A gave insoluble and soluble trypsin fragments. After dansylation, N-terminal amino acids of the trypsin-fragments were determined. Dansyl amino acids from the insoluble trypsin fragments were not identical with those from control insoluble counterparts in the membrane-spanning region of glycophorin A molecule. Fractionation by gel filtration of dansyl-soluble trypsin fragments, and the N-terminal amino acid analysis of the fractionated peptides indicated that the peptides derived from the glycosylated region located in the outside of the membrane matrix were identical with those from control soluble counterparts. The results suggest that the glycosylated outside region of glycophorin A was modified only slightly but the hydrophobic membrane-spanning region was extensively modified during membrane oxidation, most likely by oxidized lipids.
Assuntos
Membrana Eritrocítica/efeitos dos fármacos , Glicoforinas/isolamento & purificação , Peróxidos/farmacologia , Sialoglicoproteínas/isolamento & purificação , Aminoácidos/análise , Sítios de Ligação , Cromatografia de Afinidade , Cromatografia em Gel , Cromatografia Líquida de Alta Pressão , Compostos de Dansil/isolamento & purificação , Humanos , Peróxidos Lipídicos/biossíntese , Oxirredução/efeitos dos fármacos , Fragmentos de Peptídeos/isolamento & purificação , Peptídeo Hidrolases , Tripsina , terc-Butil HidroperóxidoRESUMO
The effect of recombinant interferons (rIFNs) on primary and secondary colony formation by blast progenitors (leukemic colony-forming units, L-CFU) from the peripheral blood of patients with acute myeloblastic leukemia (AML) was examined. rIFN-alpha, rIFN-beta, and rIFN-gamma inhibited L-CFU in a dose-dependent manner. When 3000 U/ml rIFN-alpha, -beta, and -gamma were added, L-CFU were suppressed to 20%, 12%, and 40% of the control cultures, respectively. The concentrations of rIFN-alpha, -beta, and -gamma required for 50% inhibition of colony formation were 63, 29, and 250 U/ml, respectively. The self-renewal capacity of L-CFU was inhibited by rIFNs in a dose-dependent manner, the degree of inhibition being the same for all three rIFNs. These rIFNs also inhibited normal granulocyte-macrophage progenitors to a similar degree as L-CFU. Taken together, these in vitro studies indicate that these rIFNs may be efficacious in the treatment of AML, though development of granulocytopenia may be observed as a complication of IFN therapy.
Assuntos
Células-Tronco Hematopoéticas/efeitos dos fármacos , Interferons/farmacologia , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Anticorpos Monoclonais/imunologia , Divisão Celular/efeitos dos fármacos , Depressão Química , Células-Tronco Hematopoéticas/patologia , Humanos , Interferons/imunologia , Células-Tronco Neoplásicas/patologia , Proteínas Recombinantes/farmacologia , Células Tumorais Cultivadas , Ensaio Tumoral de Célula-TroncoRESUMO
A new serum-free assay system for leukemic colony formation (leukemic colony-forming units, L-CFU) was established, and, utilizing this system, the colony-promoting activities of recombinant human colony-stimulating factors (rhCSFs) and the effectiveness of CSFs on cellular self-renewal capacity were investigated. The serum-free assay system included deionized bovine serum albumin (1%), cholesterol (7.8 micrograms/ml), and ASF 101 medium. The plating efficiencies obtained by culturing with phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM) ranged from 0.01% to 1.35% in this system. Spontaneous colonies were observed in 9 out of 13 cases studied. Recombinant human granulocyte CSF (rhG-CSF), rh granulocyte-macrophage CSF (rhGM-CSF), rh interleukin 3 (rhIL-3), and rh interleukin 1 (rhIL-1) stimulated colony formation in 10, 9, and 6 out of 13, and 5 out of 11 cases, respectively. The magnitude of stimulation by each CSF ranged from 6% to 145%, 21% to 200%, 0% to 1229%, and 14% to 182% of PHA-LCM, respectively. In eight cases, blast colony assays in serum-free and serum-containing cultures were simultaneously performed. The magnitudes of responsiveness of each CSF differed in the two assay systems; this indicated some effect of fetal calf serum. The value of self-renewal capacity was also examined and compared with that in serum-containing culture. Self-renewal capacity could be maintained with a serum-free culture system. It showed marked variation from case to case, and there was no correlation between the primary colony formation and the self-renewal capacity in both culture systems. Taken together, the development of a completely serum-free culture system was found to be efficient as evaluated by a L-CFU colony assay.
Assuntos
Ensaio de Unidades Formadoras de Colônias/métodos , Fatores Estimuladores de Colônias/farmacologia , Leucemia Mieloide Aguda/patologia , Sangue , Células Cultivadas , Meios de Cultura , Fator Estimulador de Colônias de Granulócitos , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Substâncias de Crescimento/farmacologia , Humanos , Interleucina-1/farmacologia , Interleucina-3/farmacologia , Leucócitos/metabolismo , Fito-Hemaglutininas/farmacologia , Proteínas Recombinantes/farmacologiaRESUMO
The colony-promoting activities of recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) and recombinant granulocyte colony-stimulating factor (rG-CSF) on primary and secondary colony formation by blast progenitors (leukemic colony-forming units [L-CFU]) from 21 patients with acute myeloblastic leukemia (AML) were examined using blast colony assay and compared to colony promotion stimulated by phytohemagglutinin-stimulated leukocyte-conditioned medium (PHA-LCM). Recombinant GM-CSF stimulated blast colonies in 13 out of 20 cases examined (1 case not done). The magnitude of stimulation by rGM-CSF varied significantly according to the type of AML, but in general was lower than that of PHA-LCM. Blast cells of type M1 did not form any colonies with rGM-CSF, although numerous colonies were produced with PHA-LCM. Type M4 blasts formed fairly large numbers of colonies, though slightly less than those stimulated by PHA-LCM. Blasts of type M2 and M5 formed colonies with the stimulation of rGM-CSF, but the numbers were considerably smaller than type M4 and those stimulated with PHA-LCM. Recombinant G-CSF stimulated blast colonies in only 5 out of 21 cases, 3 of them being type M2. The number of cases responding to rG-CSF was significantly smaller than that responding to rGM-CSF, and even in cases in which colonies were formed, the magnitude of stimulation was minimal. From these results it seems likely that blast cells of different types of AML require a different kind of CSF for their optimal growth; type M4 blasts responded to the stimulation of rGM-CSF well, but blasts of other types of AML responded poorly. Thus, except for type M4, CSF(s) other than rGM-CSF seems to be required for the sufficient growth of L-CFU. Recombinant G-CSF is not likely to play an essential role in the proliferation of leukemic blasts of most types. Previous exposure to rGM-CSF and rG-CSF did not alter the self-renewal capacity, cellular phenotype, and morphology of colony cells, indicating that the direction and degree of differentiation of L-CFU stimulated by rGM-CSF or rG-CSF were not different from those stimulated with PHA-LCM.
Assuntos
Fatores Estimuladores de Colônias/farmacologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Granulócitos , Células-Tronco Hematopoéticas/patologia , Humanos , Linfocinas/farmacologia , Macrófagos , Células-Tronco Neoplásicas/patologia , Fenótipo , Proteínas Recombinantes/farmacologia , Ensaio Tumoral de Célula-TroncoRESUMO
The CD40 molecule plays important roles in B cell activation, proliferation, and immunoglobulin (Ig) class switching. In Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines (LCL), CD40 mediates growth inhibition and EBV reactivation via the CD40 signaling pathways. CD40 cross-linking with a monoclonal antibody arrests cell growth in G1 and induces expression of p27kip1 cyclin-dependent kinase inhibitor. CD40 cross-linking also induces EBV reactivation, as detected by the induction of EBV-specific early antigen, immediate early BZLF1 RNA, and its protein product ZEBRA. These results support hypotheses that the proliferation of EBV-infected B cells in vivo can be inhibited by interactions with the CD40 ligand on activated helper T cells, and latent EBV is reactivated via the signaling pathways controlled by CD40 interactions.
Assuntos
Linfócitos B/fisiologia , Antígenos CD40/metabolismo , Proteínas de Ciclo Celular , Herpesvirus Humano 4/fisiologia , Ativação Linfocitária , Transdução de Sinais , Proteínas Supressoras de Tumor , Ativação Viral , Apoptose , Linfócitos B/efeitos dos fármacos , Linfócitos B/virologia , Ligante de CD40/metabolismo , Ciclo Celular , Linhagem Celular Transformada , Transformação Celular Viral , Inibidor de Quinase Dependente de Ciclina p27 , Herpesvirus Humano 4/genética , Humanos , Imunoglobulina M/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Latência ViralRESUMO
With the use of three different hematopoietic cell lineages, the downregulation of telomerase activity was found to be a general response to the induction of differentiation. The decrease in telomerase activity occurred as early as 24 h when HL-60 and K562 cells were cultured in the presence of 1alpha, 25 dihydroxyvitamin D3 (VD3), all-trans-retinoic acid (ATRA) and hemin, and completely disappeared after 3 days. On the other hand, MEG-01 cells showed a marked inhibition of telomerase activity after 6 days of culture with 12-0-tetradecanoylphorbal 13-acetate (TPA). The analysis of telomeric DNA in the HL-60 cells and K562 cells demonstrated no detectable loss of telomeric DNA with cellular differentiation, with a loss of telomerase activity. The repression of telomerase is a common molecular event during leukemic cell differentiation.
Assuntos
Diferenciação Celular , DNA/genética , Regulação para Baixo/efeitos dos fármacos , Telomerase/metabolismo , Telômero/genética , Sequência de Bases , Calcitriol/farmacologia , Primers do DNA , Hemina/farmacologia , Humanos , Cinética , Medições Luminescentes , Tretinoína/farmacologia , Células Tumorais CultivadasRESUMO
We investigated the proliferative effects of interleukins 1-7 (IL-1 to -7) on leukemic cells from 10 patients with T-lineage acute lymphoblastic leukemia (T-ALL). Five patients had CD7+4-8-acute leukemia, one had CD5+ acute leukemia, and four had CD1+ acute leukemia. To examine the proliferative effect of each interleukin, 3H-TdR incorporation method was used. In the presence of IL-1, no increase in 3H-TdR incorporation was observed for any of the T-ALL cells. With IL-2, 3H-TdR incorporation increased in cells from 5 out of 10 T-ALL patients, including those with CD7+4-8-, CD5+, and CD1+ acute leukemia. In the presence of IL-3 or IL-6, 3H-TdR incorporation increased in cells from 2 out of 5 patients with CD7+4-8- acute leukemia. However, CD5+ or CD1+ acute leukemia cells were not stimulated by IL-3 or IL-6. With IL-4, 3H-TdR incorporation was increased in the cells from 2 out of 5 patients with CD7+4-8- acute leukemia and in the cells of 2 of those with CD1+ acute leukemia. IL-5 increased the 3H-TdR incorporation by cells from 2 out of 5 patients with CD7+4-8- acute leukemia and 1 patient with CD1+ acute leukemia. IL-7 increased 3H-TdR incorporation in cells from all five CD7+4-8- acute leukemia and 2 of those with CD5+ or CD1+ leukemia. No synergistic effect was found when IL-7 and other cytokines were added to cells from the 3 patients with CD7+4-8- acute leukemia who were tested.