Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 7 de 7
Filtrar
1.
Cancer Sci ; 106(10): 1264-77, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26251039

RESUMO

Recent evidence has shown that deregulated expression of members of the microRNA-29 (miR-29) family may play a critical role in human cancer, including hematological malignancies. However, the roles of miR-29 in the molecular pathophysiology of T-cell acute lymphoblastic leukemia (T-ALL) has not been investigated. Here, we show that lower levels of miR-29a were significantly associated with higher blast counts in the bone marrow and with increased disease-free survival in T-ALL patients. Furthermore, miR-29a levels are extremely reduced in T-ALL cells compared to normal T cells. Microarray analysis following introduction of synthetic miR-29a mimics into Jurkat cells revealed the downregulation of several predicted targets (CDK6, PXDN, MCL1, PIK3R1, and CXXC6), including targets with roles in active and passive DNA demethylation (such as DNMT3a, DNMT3b, and members of the TET family and TDG). Restoring miR-29a levels in Jurkat and Molt-4 T-ALL cells led to the demethylation of many genes commonly methylated in T-ALL. Overall, our results suggest that reduced miR-29a levels may contribute to the altered epigenetic status of T-ALL, highlighting its relevance in the physiopathology of this disease.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Regulação Leucêmica da Expressão Gênica/genética , MicroRNAs/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Antígenos de Neoplasias/biossíntese , Apoptose/genética , Linhagem Celular Tumoral , Proliferação de Células/genética , Classe Ia de Fosfatidilinositol 3-Quinase , Quinase 6 Dependente de Ciclina/biossíntese , DNA (Citosina-5-)-Metiltransferases/genética , DNA Metiltransferase 3A , Proteínas de Ligação a DNA/biossíntese , Daunorrubicina/farmacologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Células Jurkat , Oxigenases de Função Mista , Proteína de Sequência 1 de Leucemia de Células Mieloides/biossíntese , Análise de Sequência com Séries de Oligonucleotídeos , Peroxidases , Fosfatidilinositol 3-Quinases/biossíntese , Proteínas Proto-Oncogênicas/biossíntese , Receptores de Interleucina-1/biossíntese , DNA Metiltransferase 3B
2.
Proc Natl Acad Sci U S A ; 106(4): 1187-92, 2009 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-19147845

RESUMO

Loss-of-function mutations in telomerase complex genes can cause bone marrow failure, dyskeratosis congenita, and acquired aplastic anemia, both diseases that predispose to acute myeloid leukemia. Loss of telomerase function produces short telomeres, potentially resulting in chromosome recombination, end-to-end fusion, and recognition as damaged DNA. We investigated whether mutations in telomerase genes also occur in acute myeloid leukemia. We screened bone marrow samples from 133 consecutive patients with acute myeloid leukemia and 198 controls for variations in TERT and TERC genes. An additional 89 patients from a second cohort, selected based on cytogenetic status, and 528 controls were further examined for mutations. A third cohort of 372 patients and 384 controls were specifically tested for one TERT gene variant. In the first cohort, 11 patients carried missense TERT gene variants that were not present in controls (P < 0.0001); in the second cohort, TERT mutations were associated with trisomy 8 and inversion 16. Mutation germ-line origin was demonstrated in 5 patients from whom other tissues were available. Analysis of all 3 cohorts (n = 594) for the most common gene variant (A1062T) indicated a prevalence 3 times higher in patients than in controls (n = 1,110; P = 0.0009). Introduction of TERT mutants into telomerase-deficient cells resulted in loss of enzymatic activity by haploinsufficiency. Inherited mutations in TERT that reduce telomerase activity are risk factors for acute myeloid leukemia. We propose that short and dysfunctional telomeres limit normal stem cell proliferation and predispose for leukemia by selection of stem cells with defective DNA damage responses that are prone to genome instability.


Assuntos
Leucemia Mieloide Aguda/enzimologia , Leucemia Mieloide Aguda/genética , Mutação/genética , Telomerase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Estudos de Casos e Controles , Linhagem Celular , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Telomerase/química , Telômero/metabolismo
3.
Br J Haematol ; 144(2): 223-9, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19016721

RESUMO

Some cases of T-cell acute lymphoblastic leukaemia (ALL) express markers found in natural-killer (NK) cells, such as CD56 and CD16. Out of 84 T-cell ALL cases diagnosed at our Institution, CD56 and/or CD16 was detected in 24 (28.5%), which we designated T/NK-ALL group. Clinical features, laboratory characteristics, survival and expression of cytotoxic molecules were compared in T/NK-ALL and T-ALL patients. Significant differences were observed regarding age (24.9 vs. 16.4 years in T/NK-ALL and T-ALL, respectively, P = 0.006) and platelet counts (177 x 10(9)/l vs. 75 x 10(9)/l in T/NK-ALL and T-ALL, respectively, P = 0.03). Immunophenotypic analysis demonstrated that CD34, CD45RA and CD33 were more expressed in T/NK-ALL patients, whereas CD8 and terminal deoxynucleotidyl transferase were more expressed in T-ALL patients (P < 0.05). The mean overall survival (863 vs. 1869 d, P = 0.02) and disease-free survival (855 vs. 2095 d, P = 0.002) were shorter in patients expressing CD56/CD16. However, multivariate analysis identified CD56/CD16 as an independent prognostic factor only for DFS. Cytotoxic molecules were highly expressed in T/NK-ALL compared to T-ALL. Perforin, granzyme B and TIA-1 were detected in 12/17, 4/17 and 7/24 T/NK-ALL patients and in 1/20, 0/20 and 1/20 T-ALL respectively (P < 0.001, P = 0.036 and P = 0.054). Therefore, the presence of CD56/CD16 was associated with distinct clinical features and expression of cytotoxic molecules in the blasts.


Assuntos
Antígeno CD56/análise , Células Matadoras Naturais/imunologia , Leucemia-Linfoma Linfoblástico de Células T Precursoras/imunologia , Receptores de IgG/análise , Adolescente , Adulto , Fatores Etários , Antígenos CD/análise , Antígenos CD34/análise , Antígenos de Diferenciação Mielomonocítica/análise , Biomarcadores/análise , Complexo CD3/análise , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Granzimas/análise , Humanos , Imunofenotipagem , Estimativa de Kaplan-Meier , Antígenos Comuns de Leucócito/análise , Masculino , Perforina/análise , Contagem de Plaquetas , Proteínas de Ligação a Poli(A)/análise , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/mortalidade , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Taxa de Sobrevida , Antígeno-1 Intracelular de Células T , Resultado do Tratamento , Adulto Jovem
4.
J Leukoc Biol ; 82(5): 1340-3, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-17704297

RESUMO

The use of all trans-retinoic acid (ATRA) is the basis of treatment of acute promyelocytic leukemia (APL) and represents the paradigm of differentiation therapy. In general, ATRA is well-tolerated but may be associated with a potentially lethal side-effect, referred to as retinoic acid or differentiation syndrome (DS). The cellular and molecular mechanisms of DS are poorly understood and involve changes in the adhesive qualities and cytokine secretion of leukemic cells during ATRA-induced differentiation. As leukocyte extravasation is a key event in DS pathogenesis, we analyzed the association between the polymorphisms at Exon 4 (G241R) and Exon 6 (E469K) of ICAM-1 and Exon 3 (L125V) of PECAM-1 genes with DS development in APL patients treated with ATRA and anthracyclines. DS was diagnosed in 23/127 (18.1%) APL patients at an average of 11.5 days after the start of ATRA. All patients presented respiratory distress associated with increased ground-glass opacity in chest radiographies. Other accompanying symptoms were: fever not attributable to infection (65.2%), generalized edema (37.5%), weight gain (37.5%), and impairment of renal function (8.6%). We detected an association between development of DS and the AA genotype at Codon 469 of ICAM-1 (odds ratio of 3.5; 95% confidence interval: 1.2-10.2). Conversely, no significant association was detected between G241R or L125V polymorphisms at Exon 4 of ICAM-1 and Exon 3 of PECAM-1, respectively. Our results suggest that susceptibility to DS in APL patients may be influenced by genetic variation in adhesion molecule loci.


Assuntos
Éxons/genética , Molécula 1 de Adesão Intercelular/genética , Leucemia Promielocítica Aguda/genética , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Polimorfismo Genético/genética , Adulto , Antineoplásicos/efeitos adversos , Diferenciação Celular , Diagnóstico Diferencial , Feminino , Humanos , Leucemia Promielocítica Aguda/complicações , Leucemia Promielocítica Aguda/diagnóstico , Masculino , Síndrome , Tretinoína/efeitos adversos
5.
Exp Hematol Oncol ; 2(1): 10, 2013 Apr 08.
Artigo em Inglês | MEDLINE | ID: mdl-23566596

RESUMO

BACKGROUND: CD56 expression has been associated with a poor prognosis in lymphoid neoplasms, including T-cell acute lymphoblastic leukemia (T-ALL). MicroRNAs (miRNAs) play an important role in lymphoid differentiation, and aberrant miRNA expression has been associated with treatment outcome in lymphoid malignancies. Here, we evaluated miRNA expression profiles in normal thymocytes, mature T-cells, and T-ALL samples with and without CD56 expression and correlated microRNA expression with treatment outcome. METHODS: The gene expression profile of 164 miRNAs were compared for T-ALL/CD56+ (n=12) and T-ALL/CD56- (n=36) patients by Real-Time Quantitative PCR. Based on this analysis, we decided to evaluate miR-221 and miR-374 expression in individual leukemic and normal samples. RESULTS: miR-221 and miR-374 were expressed at significantly higher levels in T-ALL/CD56+ than in T-ALL/CD56- cells and in leukemic blasts compared with normal thymocytes and peripheral blood (PB) T-cells. Age at diagnosis (15 or less vs grater than 15 years; HR: 2.19, 95% CI: 0.98-4.85; P=0.05), miR-221 expression level (median value as cut off in leukemic samples; HR: 3.17, 95% CI: 1.45-6.92; P=0.004), and the expression of CD56 (CD56-vs CD56+; HR: 2.99, 95% CI: 1.37-6.51; P=0.006) were predictive factors for shorter overall survival; whereas, only CD56 expression (HR: 2.73, 95% CI: 1.03-7.18; P=0.041) was associated with a shorter disease-free survival rate. CONCLUSIONS: miR-221 is highly expressed in T-ALL and its expression level may be associated with a poorer prognosis.

6.
Leuk Res ; 35(5): 657-62, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21168913

RESUMO

Indole-3-acetic acid (IAA), when oxidized by horseradish peroxidase (HRP), is transformed into cytotoxic molecules capable of inducing cell injury. The aim of this study was to test if, by targeting hematopoietic tumors with HRP-conjugated antibodies in association with IAA treatment, there is induction of apoptosis. We used two lineages of hematologic tumors: NB4, derived from acute promyelocytic leukemia (APL) and Granta-519 from mantle cell lymphoma (MCL). We also tested cells from 12 patients with acute myeloid leukemia (AML) and from 10 patients with chronic lymphocytic leukemia (CLL). HRP targeting was performed with anti-CD33 or anti-CD19 antibodies (depending on the origin of the cell), followed by incubation with goat anti-mouse antibody conjugated with HRP. Eight experimental groups were analyzed: control, HRP targeted, HRP targeted and incubated with 1, 5 and 10mM IAA, and cells not HRP targeted but incubated with 1, 5 and 10mM IAA. Apoptosis was analyzed by flow cytometry using annexin V-FITC and propidium iodide labeling. Results showed that apoptosis was dependent on the dose of IAA utilized, the duration of exposure to the prodrug and the origin of the neoplasia. Targeting HRP with antibodies was efficient in activating IAA and inducing apoptosis.


Assuntos
Anticorpos/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias Hematológicas/patologia , Ácidos Indolacéticos/farmacologia , Adolescente , Adulto , Anticorpos/química , Apoptose/fisiologia , Técnicas de Cultura de Células , Linhagem da Célula/efeitos dos fármacos , Linhagem da Célula/fisiologia , Estudos de Coortes , Sistemas de Liberação de Medicamentos/métodos , Feminino , Peroxidase do Rábano Silvestre/metabolismo , Peroxidase do Rábano Silvestre/farmacologia , Humanos , Imunotoxinas/química , Imunotoxinas/farmacologia , Ácidos Indolacéticos/química , Masculino , Pessoa de Meia-Idade , Células Tumorais Cultivadas
7.
Cytometry B Clin Cytom ; 74(3): 163-8, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18200595

RESUMO

BACKGROUND: The most primitive leukemic precursor in acute myeloid leukemia (AML) is thought to be the leukemic stem cell (LSC), which retains the properties of self-renewal and high proliferative capacity and quiescence of the hematopoietic stem cell. LSC seems to be immunophenotypically distinct and more resistant to chemotherapy than the more committed blasts. Considering that the multidrug resistance (MDR) constitutive expression may be a barrier to therapy in AML, we have investigated whether various MDR transporters were differentially expressed at the protein level by different leukemic subsets. METHODS: The relative expression of the drug-efflux pumps P-gp, MRP, LRP, and BCRP was evaluated by mean fluorescence index (MFI) and the Kolmogorov-Smirnov analysis (D values) in five leukemic subpopulations: CD34+CD38-CD123+ (LSCs), CD34+CD38+CD123-, CD34+CD38+CD123+, CD34+CD38+CD123-, and CD34- mature cells in 26 bone marrow samples of CD34+ AML cases. RESULTS: : The comparison between the two more immature subsets (LSC versus CD34+CD38-CD123- cells) revealed a higher P-gp, MRP, and LRP expression in LSCs. The comparative analysis between LSCs and subsets of intermediate maturation (CD34+CD38+) demonstrated the higher BCRP expression in the LSCs. In addition, P-gp expression was also significantly higher in the LSC compared to CD34+CD38+CD123- subpopulation. Finally, the comparative analysis between LSC and the most mature subset (CD34-) revealed higher MRP and LRP and lower P-gp expression in the LSCs. CONCLUSIONS: Considering the cellular heterogeneity of AML, the higher MDR transporters expression at the most immature, self-renewable, and quiescent LSC population reinforces that MDR is one of the mechanisms responsible for treatment failure.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Partículas de Ribonucleoproteínas em Forma de Abóbada/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Diferenciação Celular , Resistencia a Medicamentos Antineoplásicos , Citometria de Fluxo/métodos , Humanos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Células-Tronco Neoplásicas/classificação , Células-Tronco Neoplásicas/patologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA