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2.
Mutagenesis ; 34(3): 245-252, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31037299

RESUMO

Genomic instability is a hallmark of cancer, contributing to tumour development and transformation, being chromosome instability (CIN) the most common form in human cancer. Chronic lymphocytic leukaemia (CLL) is the most frequent adult leukaemia in the Western world. In this study, we have evaluated basal CIN in untreated patients with CLL by measuring chromosome aberrations (CAs) and micronucleus (MN) frequency and their association with different prognostic factors. Seventy-two patients and 21 normal controls were analysed. Cytogenetic and fluorescence in situ hybridisation (FISH) studies were performed. IGHV (immunoglobulin heavy chain variable region) mutational status was evaluated by reverse transcription polymerase chain reaction and sequencing. An increased number of CA in patients compared with controls (P = 0.0001) was observed. Cases with abnormal karyotypes showed increased CA rate than those with normal karyotypes (P = 0.0026), with a particularly highest frequency in cases with complex karyotypes. Among FISH risk groups, a significant low frequency of CA was found in patients with no FISH alterations compared to those with del13q14 and ≥2 FISH alterations (P = 0.0074). When mean CA value (6.7%) was considered, significant differences in the distribution of low and high CA frequency between cases with normal and abnormal karyotypes (P = 0.002) were observed. By MN analysis, higher frequency in patients compared to controls (P = 0.0001) was also found, as well as between cases with ≥2 FISH abnormalities and those with no FISH alterations (P = 0.026). Similarly, significant differences were observed when patients were divided according to mean MN frequency (2.2%; P ≤ 0.04). Interestingly, patients with high MN frequency had shorter time to first treatment than those with low frequency (P = 0.024). Cases with mutated and unmutated IGHV status showed increased CA and MN frequencies compared to controls (P ≤ 0.0007), but no differences between both groups were found. Our results support the strong interaction between CIN and genomic complexity as well as their influence on poor outcome in this pathology.

3.
Salud(i)ciencia (Impresa) ; 23(4): 332-338, mar. 2019. tab, graf
Artigo em Espanhol | LILACS, BINACIS | ID: biblio-1010189

RESUMO

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. The disease has\r\na highly variable clinical course, ranging from very indolent cases to patients with aggressive and rapidly\r\nprogressing outcome. Genetic studies are useful tools in analyzing this pathology, and have been incorporated in international risk classifications. The analysis of genomic rearrangements and the mutational status of immunoglobulin heavy chain variable have allowed risk groups of high prognostic value to be established. More recently, next generation sequencing studies have identified novel somatic mutations that could explain the wide clinical variability of this pathology. Among them, the analysis of NOTCH1 (neurogenic locus notch homolog protein 1) gene mutations are of interest, as deregulation is associated with tumorigenesis. NOTCH11 mutations are mostly located at exon 34 (80% of cases) and 3´UTR (untranslated region). They produce premature stop codons that produce a constitutively active and stable NOTCH1 protein. NOTCH1 mutations are associated with adverse prognosis and refractoriness to treatment. The aim of this study was to analyze NOTCH1 mutations in CLL patients by ASO-PCR and sequencing. Our results found 4.4% of cases with NOTCH1 mutated values concordant with international observations (5%-10%). Including them in the genetic status of CLL patients allows the characterization of risk groups, an aspect of great importance in clinical practice and therapeutic decisions, to be refined.


La leucemia linfocítica crónica (LLC) es la leucemia más frecuente en adultos de Occidente. Presenta\r\nun curso clínico altamente variable, con pacientes que requieren tratamiento inmediato y otros con un curso indolente de la enfermedad. Los estudios genéticos constituyen herramientas de suma utilidad en esta enfermedad, encontrándose incorporados a las clasificaciones de riesgo internacionales. El análisis de los rearreglos genómicos y del estado mutacional de los genes IGHV (immunoglobulin heavy chain variable region) ha hecho factible establecer grupos de riesgo de alto valor pronóstico. Más recientemente, estudios de secuenciación de última generación permitieron la detección de mutaciones\r\nsomáticas previamente desconocidas en esta afección, que podrían explicar la amplia variabilidad clínica\r\nobservada en la LLC. Entre ellas, resultan de interés las observadas en el gen NOTCH1 (neurogenic locus notch homolog protein 1), cuya desregulación se asocia con el desarrollo tumoral. Estas mutaciones se acumulan en mayor medida en el exón 34 (80% de los casos) y en la región 3´UTR (untraslated region), lo que genera codones de terminación prematuros que originan una proteína NOTCH1 constitutivamente activa y más estable, los cuales se asocian con pronóstico adverso y refractariedad al tratamiento. Nuestro objetivo fue evaluar mutaciones de NOTCH1 en nuestros pacientes mediante ASO-PCR y secuenciación. Se detectaron mutaciones en el 4.4% de los casos, valor concordante con los datos internacionales (5% a 10%). Su inclusión en la caracterización genética de los pacientes con LLC permitirá refinar la categorización de los grupos de riesgo, aspecto de suma importancia tanto en el seguimiento clínico como en la toma de decisiones terapéuticas.


Assuntos
Humanos , Leucemia Linfocítica Crônica de Células B , Citogenética , Receptor Notch1 , Mutação/genética
4.
Br J Haematol ; 184(3): 373-383, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30565652

RESUMO

Long non-coding RNAs (lncRNAs) comprise a family of non-coding transcripts that are emerging as relevant gene expression regulators of different processes, including tumour development. To determine the possible contribution of lncRNA to the pathogenesis of follicular lymphoma (FL) we performed RNA-sequencing at high depth sequencing in primary FL samples ranging from grade 1-3A to aggressive grade 3B variants using unpurified (n = 16) and purified (n = 12) tumour cell suspensions from nodal samples. FL grade 3B had a significantly higher number of differentially expressed lncRNAs (dif-lncRNAs) with potential target coding genes related to cell cycle regulation. Nine out of the 18 selected dif-lncRNAs were validated by quantitative real time polymerase chain reaction in an independent series (n = 43) of FL. RP4-694A7.2 was identified as the top deregulated lncRNA potentially involved in cell proliferation. RP4-694A7.2 silencing in the WSU-FSCCL FL cell line reduced cell proliferation due to a block in the G1/S phase. The relationship between RP4-694A7.2 and proliferation was confirmed in primary samples as its expression levels positively related to the Ki-67 proliferation index. In summary, lncRNAs are differentially expressed across the clinico-biological spectrum of FL and a subset of them, related to cell cycle, may participate in cell proliferation regulation in these tumours.


Assuntos
Pontos de Checagem da Fase G1 do Ciclo Celular , Regulação Neoplásica da Expressão Gênica , Linfoma Folicular/metabolismo , RNA Longo não Codificante/biossíntese , RNA Neoplásico/biossíntese , Pontos de Checagem da Fase S do Ciclo Celular , Feminino , Humanos , Linfoma Folicular/genética , Linfoma Folicular/patologia , Masculino , RNA Longo não Codificante/genética , RNA Neoplásico/genética
8.
PLoS One ; 12(6): e0179883, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28666010

RESUMO

Telomeres are protective repeats of TTAGGG sequences located at the end of human chromosomes. They are essential to maintain chromosomal integrity and genome stability. Telomerase is a ribonucleoprotein complex containing an internal RNA template (hTR) and a catalytic subunit (hTERT). The human hTR gene consists of three major domains; among them the H/ACA domain is essential for telomere biogenesis. H/ACA ribonucleoprotein (RNP) complex is composed of four evolutionary conserved proteins, including dyskerin (encoded by DKC1 gene), NOP10, NHP2 and GAR1. In this study, we have evaluated the expression profile of the H/ACA RNP complex genes: DKC1, NOP10, NHP2 and GAR1, as well as hTERT and hTR mRNA levels, in patients with chronic lymphocytic leukemia (CLL). Results were correlated with the number and type of genetic alteration detected by conventional cytogenetics and FISH (fluorescence in situ hybridization), IGHV (immunoglobulin heavy chain variable region) mutational status, telomere length (TL) and clinico-pathological characteristics of patients. Our results showed significant decreased expression of GAR1, NOP10, DKC1 and hTR, as well as increased mRNA levels of hTERT in patients compared to controls (p≤0.04). A positive correlation between the expression of GAR1-NHP2, GAR1-NOP10, and NOP10-NHP2 (p<0.0001), were observed. The analysis taking into account prognostic factors showed a significant increased expression of hTERT gene in unmutated-IGHV cases compared to mutated-CLL patients (p = 0.0185). The comparisons among FISH groups exhibited increased expression of DKC1 in cases with two or more alterations with respect to no abnormalities, trisomy 12 and del13q14, and of NHP2 and NOP10 compared to those with del13q14 (p = 0.03). The analysis according to TL showed a significant increased expression of hTERT (p = 0.0074) and DKC1 (p = 0.0036) in patients with short telomeres compared to those with long TL. No association between gene expression and clinical parameters was found. Our results suggest a role for these telomere associated genes in genomic instability and telomere dysfunction in CLL.


Assuntos
Leucemia Linfocítica Crônica de Células B/metabolismo , Ribonucleoproteínas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Perfilação da Expressão Gênica , Humanos , Hibridização in Situ Fluorescente , Leucemia Linfocítica Crônica de Células B/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Telômero
10.
PLoS One ; 12(4): e0174945, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28384193

RESUMO

INTRODUCTION: Obesity is the principal component in the Metabolic Syndrome (MetS) that determines the progression of metabolic complications. Metabolically healthy obese (MHO) individuals seem to be protected against those complications. Telomere length (TL) as a novel marker of cellular aging had a complex relationship to the MetS. The principal aim of this study was to investigate the TL in MHO, and to study the association between TL and the worsening of the metabolic condition. MATERIAL AND METHODS: We have determined the absolute TL (aTL) in 400 women (mean age of 46.76 ± 15.47 years; range: 18-86 years), grouped according to the metabolic condition in three groups: metabolically healthy non-obese women (MHNO), MHO and obese women with MetS (MSO); and grouped according to the number of components of MetS. RESULTS: We found that MHO displays significantly higher aTL than MSO (p = 0.033; r = -4.63; 95% CI r = -8.89 / -0.37), but did not differ from MHNO. A decrease in aTL with the progressive increase in the number of MetS components was also observed (p < 0.001; r = -2.06; 95% CI r = -3.13 / -0.99). In this way, our results indicate that aTL is influenced by the presence of MetS, but it is not affected by the presence of obesity. DISCUSSION: We found that shorter aTL is not associated with MHO, but is related to MetS and with the increased number of metabolic abnormalities.


Assuntos
Síndrome Metabólica/genética , Obesidade Metabolicamente Benigna/genética , Telômero , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Adulto Jovem
11.
Front Biosci (Schol Ed) ; 9: 17-30, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27814571

RESUMO

Telomeres are highly regulated and dynamic complexes that protect the genomic DNA and prevent the end of linear chromosomes from being misrecognized as a broken DNA. Due to the end replication problem, telomeres of somatic cells shorten with each cell division, inducing cell senescence. Telomerase is a reverse transcriptase capable of compensating telomere attrition by adding telomere repeats to the ends of chromosomes. Human telomeres are associated with the shelterin complex which consists of six telomere-associated proteins that specifically bind to telomeric DNA. Alterations or removal of individual shelterin components would lead to telomere uncapping and telomere dysfunction, resulting in cellular senescence and transformation to a malignant state. Another complex of multifunctional proteins, named non-shelterin complex, is thought to prevent telomere degradation and facilitate telomerase-based telomere elongation. As telomerase is highly expressed in most human tumor cells, it is considered an attractive target for new therapeutic strategies. In this review, we will summarize the characteristics of telomeres and telomerase in lymphoid malignancies and discuss the role of telomere-associated proteins in these entities.


Assuntos
Neoplasias Hematológicas/genética , Neoplasias Hematológicas/metabolismo , Telômero/genética , Telômero/metabolismo , Animais , Senescência Celular/genética , Neoplasias Hematológicas/patologia , Humanos , Telomerase/genética , Telomerase/metabolismo
12.
Ann Hum Biol ; 44(4): 379-383, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27892694

RESUMO

BACKGROUND: Glutathione S-transferases (GSTs) are drug-metabolising enzymes involved in biotransformation of carcinogens, drugs, xenobiotics and oxygen free radicals. Polymorphisms of GST genes contribute to inter-individual and population variability in the susceptibility to environmental risk factors, cancer predisposition and pharmacotherapy responses. However, data about GST variability in Argentina are lacking. AIM: The purpose was to determine the prevalence of GSTM1, GSTT1 and GSTP1 polymorphisms in the general population from a central region of Argentina and to perform inter-population comparisons. SUBJECTS AND METHODS: GSTM1 and GSTT1 gene deletions and GSTP1 c.313A > G were genotyped by PCR assays in 609 healthy and unrelated Argentinians. RESULTS: The frequencies of variant genotypes in Argentinians were GSTM1-null (45%), GSTT1-null (17%) and GSTP1-GG (11%). GSTM1-present genotype was significantly associated with GSTP1-AG or GSTP1-GG variants (p = 0.037; p = 0.034, respectively). Comparison with worldwide populations demonstrated that the GST distributions in Argentina are similar to those reported for Italy and Spain, whereas significant differences were observed regarding Asian and African populations (p < 0.001). CONCLUSION: This study has determined, for the first time, the normative profile of three pharmacogenetically relevant polymorphisms (GSTM1, GSTT1 and GSTP1) in the largest Argentinian cohort described to date, providing the basis for further epidemiological and pharmacogenetic studies in this country.


Assuntos
Glutationa S-Transferase pi/genética , Glutationa Transferase/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Argentina , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Adulto Jovem
13.
Cancer Immunol Immunother ; 66(4): 461-473, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28011996

RESUMO

Small molecules targeting kinases involved in B cell receptor signaling are showing encouraging clinical activity in chronic lymphocytic leukemia (CLL) patients. Fostamatinib (R406) and entospletinib (GS-9973) are ATP-competitive inhibitors designed to target spleen tyrosine kinase (Syk) that have shown clinical activity with acceptable toxicity in trials with CLL patients. Preclinical studies with these inhibitors in CLL have focused on their effect in patient-derived leukemic B cells. In this work we show that clinically relevant doses of R406 and GS-9973 impaired the activation and proliferation of T cells from CLL patients. This effect could not be ascribed to Syk-inhibition given that we show that T cells from CLL patients do not express Syk protein. Interestingly, ζ-chain-associated protein kinase (ZAP)-70 phosphorylation was diminished by both inhibitors upon TCR stimulation on T cells. In addition, we found that both agents reduced macrophage-mediated phagocytosis of rituximab-coated CLL cells. Overall, these results suggest that in CLL patients treated with R406 or GS-9973 T cell functions, as well as macrophage-mediated anti-tumor activity of rituximab, might be impaired. The potential consequences for CLL-treated patients are discussed.


Assuntos
Indazóis/farmacologia , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Macrófagos/imunologia , Oxazinas/farmacologia , Pirazinas/farmacologia , Piridinas/farmacologia , Quinase Syk/antagonistas & inibidores , Linfócitos T/efeitos dos fármacos , Proteína-Tirosina Quinase ZAP-70/metabolismo , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Feminino , Humanos , Ativação Linfocitária/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Fagocitose/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Receptores de Antígenos de Linfócitos T/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Rituximab/farmacologia , Linfócitos T/imunologia
14.
Tumour Biol ; 37(10): 13637-13647, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27473081

RESUMO

Mycosis fungoides is the most common type of primary cutaneous T cell lymphoma. We have evaluated CDKN2A losses and MYC gains/amplifications by FISH analysis, as well as expression of miR-155 and members of the oncogenic cluster miR-17-92 (miR17, miR18a, miR19b, and miR92a) in MF patients with advanced disease. Formalin-fixed paraffin-embedded skin biopsies from 36 patients at diagnosis, 16 with tumoral MF (T-MF), 13 in histological transformation to a large T cell lymphoma (TR-MF), and 7 cases with folliculotropic variant (F-MF), were studied. Twenty cases showed genomic alterations (GAs): 8 (40 %) had CDKN2A deletion, 7 (35 %) showed MYC gain, and 5 (25 %) exhibited both alterations. GAs were more frequently observed in F-MF (p = 0.004) and TR-MF (p = 0.0001) than T-MF. GAs were significantly higher in cases presenting lesions in head, neck, and lower extremities compared to those observed in trunk and upper extremities (p = 0.03), when ≥25 % neoplastic cells were CD30 positive (p = 0.016) as well as in cases with higher Ki-67 proliferation index (p = 0.003). Patients with GAs showed bad response to treatment (p = 0.02) and short survival (p = 0.04). Furthermore, MF patients showed higher miRNA expression compared to controls (p ≤ 0.0223). T-MF showed higher miR17 and miR-18a expression compared to F-MF and TR-MF (p ≤ 0.0387) while miR19b, miR92a, and miR-155 showed increased levels in F-MF and TR-MF with respect to T-MF (p ≤ 0.0360). Increased expression of miR17 and miR19b in GA group compared to cases without alterations (p ≥ 0.0307) was also detected. Our results add new information about genomic imbalances in MF patients, particularly in F-MF, and extend the present view of miRNA deregulation in this disease.


Assuntos
Biomarcadores Tumorais/genética , Instabilidade Genômica , Linfoma Cutâneo de Células T/genética , MicroRNAs/genética , Micose Fungoide/genética , Neoplasias Cutâneas/genética , Transcriptoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 8/genética , Cromossomos Humanos Par 9/genética , Feminino , Seguimentos , Genômica/métodos , Humanos , Hibridização in Situ Fluorescente , Linfoma Cutâneo de Células T/patologia , Masculino , Pessoa de Meia-Idade , Micose Fungoide/patologia , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias Cutâneas/patologia
15.
Genes Chromosomes Cancer ; 55(6): 531-40, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26998831

RESUMO

Mantle cell lymphoma (MCL) is a heterogeneous B-cell lymphoid malignancy where most patients follow an aggressive clinical course whereas others are associated with an indolent performance. SOX4, SOX11, and SOX12 belong to SOXC family of transcription factors involved in embryonic neurogenesis and tissue remodeling. Among them, SOX11 has been found aberrantly expressed in most aggressive MCL patients, being considered a reliable biomarker in the pathology. Several studies have revealed that microRNAs (miRs) from the miR-17-92 cluster are among the most deregulated miRNAs in human cancers, still little is known about this cluster in MCL. In this study we screened the transcriptional profiles of 70 MCL patients for SOXC cluster and miR17, miR18a, miR19b and miR92a, from the miR-17-92 cluster. Gene expression analysis showed higher SOX11 and SOX12 levels compared to SOX4 (P ≤ 0.0026). Moreover we found a negative correlation between the expression of SOX11 and SOX4 (P < 0.0001). miR17-92 cluster analysis showed that miR19b and miR92a exhibited higher levels than miR17 and miR18a (P < 0.0001). Unsupervised hierarchical clustering revealed two subgroups with significant differences in relation to aggressive MCL features, such as blastoid morphological variant (P = 0.0412), nodal presentation (P = 0.0492), CD5(+) (P = 0.0004) and shorter overall survival (P < 0.0001). Together, our findings show for the first time an association between the differential expression profiles of SOXC and miR17-92 clusters in MCL and also relate them to different clinical subtypes of the disease adding new biological information that may contribute to a better understanding of this pathology. © 2016 Wiley Periodicals, Inc.


Assuntos
Linfoma de Célula do Manto/genética , MicroRNAs/genética , Fatores de Transcrição SOXC/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proliferação de Células/genética , Análise por Conglomerados , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Linfoma de Célula do Manto/patologia , Masculino , MicroRNAs/biossíntese , Análise em Microsséries , Pessoa de Meia-Idade , Fatores de Transcrição SOXC/biossíntese , Análise de Sobrevida
16.
Rev. argent. endocrinol. metab ; 53(1): 22-28, mar. 2016. graf, tab
Artigo em Espanhol | LILACS-Express | ID: biblio-957937

RESUMO

La obesidad es el principal componente del síndrome metabólico (SM) y determina la progresión de la enfermedad a las complicaciones metabólicas. Los individuos obesos metabólicamente sanos (OMS) parecen estar protegidos contra esas complicaciones. La longitud de los telómeros (LT) es un nuevo marcador del envejecimiento celular, que tiene una relación compleja con el SM. El objetivo principal de este estudio fue investigar por primera vez la LT en OMS y estudiar la asociación entre LT y el número de componentes del SM. Se estudió a 398 mujeres con una edad media de 46,76 ± 15,47 años (rango: 18-86 años), que se agruparon en: individuos con normopeso sin ningún componente del SM (NP0), obesos sin SM (OMS) y de acuerdo con el número de componentes de SM en los grupos sin ningún componentes de SM (0), con uno o 2 componentes (1 + 2) y con SM por la presencia de 3 o más componentes (SM). La LT de los OMS no se diferenció de la de los NP0, pero fue significativamente mayor que la de los individuos con SM (p = 0,032). Se observó una disminución de la LT con el aumento progresivo del número de componentes del SM (p = 0,004), en donde el grupo 0 presentó una LT significativamente mayor que los grupos 1 + 2 (p = 0,027) y SM (p = 0,003). Demostramos por primera vez que las mujeres OMS presentan una LT similar a las mujeres NP0 y más larga que aquellas mujeres con SM. Además, confirmamos que la LT se acorta con el aumento en el número de alteraciones del SM.


Obesity is the principal component in Metabolic Syndrome (MetS) and determines the progression of metabolic complications. Metabolically healthy obese individuals (MHO) seem to be protected against those complications. Telomere length (TL), as a novel marker of cellular aging, has a complex relationship with MetS. The principal aim of this study was to investigate TL in MHO, and to study the association between TL and the number of MetS components. A study was conducted on 398 women (mean age: 46.76 ± 15.47 years; range: 18 - 86 years), grouped according to the number of MetS components (0, 1 + 2, MetS), a group of normal-weight individuals with 0 MetS components (NW0), and a group of obese without MetS (MHO). No differences were found in the TL of the MHO group compared to the NW0, but it was significantly higher than that of individuals with MetS (P = .032). A decrease in TL was observed with a progressive increase in the number of MetS components (P = .004), whereas the group of individuals without MetS components had significantly longer TL than the groups with 1 and 2 components (P = .027), and MetS (P = .003). Shorter TL is not associated with MHO, but is related to MetS and with an increased number of metabolic abnormalities.

17.
Cancer Genet ; 209(4): 166-70, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26883452

RESUMO

Translocation t(4;11)(q21;p15) is a rare recurrent change associated to T-cell acute leukemia. In most cases, this alteration appears as the only abnormality or as part of a simple karyotype. In this report, we present the first case of T acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) with the unbalanced translocation der(11)t(4;11)(q21;p15) as part of a very complex karyotype with multiple chromosome abnormalities, most of them not previously described in the literature. FISH (fluorescence in situ hybridization) and spectral karyotype (HiSKY) analysis confirmed the presence of complex alterations. The patient, a 16-year-old male, showed poor response to treatment and short survival (11 months). A detailed review of previously reported cases with t(4;11)(q21;p15) is also provided. The description of this type of alterations may contribute to the identification of new molecular mechanism associated to neoplastic development.


Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 4 , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética , Adolescente , Citogenética/métodos , Humanos , Masculino
18.
Am J Hematol ; 91(5): 481-5, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26852175

RESUMO

Mantle cell lymphoma (MCL) is an aggressive lymphoid neoplasm with poor prognosis. Acquired telomerase reverse transcriptase gene promoter (TERTp) mutations are among the most frequent somatic non-coding mutations in cancers. In this study, the prevalence of TERTp mutations in 24 MCL and 21 other lymphoid neoplasias (oLN) was investigated. Eight MCL samples (33%) carried TERTp mutations, two homozygous and six heterozygous (seven C228T and one C250T), which directly correlated with higher TERT transcription, mitochondrial DNA copy number, and IGHV mutational status in MCL neoplastic cells. TERTp mutations were not found in oLN. TERTp mutations correlated with more lymphoma proliferation and tumor burden, as suggested by the higher number of lymphoma cells circulating in peripheral blood, and tended to associate with longer MCL telomeres, especially in homozygous mutants, although not statistically significant. Telomere-biology genes were overexpressed in MCL cells in comparison to healthy lymphocytes, but were not influenced by mutation status. The findings described for the first time that acquired TERTp mutations are common in MCL but not in other lymphoid neoplasms. It was also demonstrated that TERTp mutations are associated with higher TERT mRNA expression in MCL cells in vivo and higher tumor burden, suggesting these mutations as a driver event in MCL development and progression.


Assuntos
Regulação Neoplásica da Expressão Gênica/genética , Linfoma de Célula do Manto/genética , Mutação Puntual , Regiões Promotoras Genéticas/genética , Telomerase/genética , Transcrição Genética , Idoso , Idoso de 80 Anos ou mais , Divisão Celular , DNA Mitocondrial/análise , DNA de Neoplasias/genética , Progressão da Doença , Feminino , Dosagem de Genes , Genótipo , Humanos , Cadeias Pesadas de Imunoglobulinas/genética , Região Variável de Imunoglobulina/genética , Leucemia/genética , Linfoma/genética , Masculino , Pessoa de Meia-Idade , Telômero/ultraestrutura , Carga Tumoral , Macroglobulinemia de Waldenstrom/genética
20.
Brain Pathol ; 26(1): 43-61, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25808628

RESUMO

Although BMP4-induced differentiation of glioma stem cells (GSCs) is well recognized, details of the cellular responses triggered by this morphogen are still poorly defined. In this study, we established several GSC-enriched cell lines (GSC-ECLs) from high-grade gliomas. The expansion of these cells as adherent monolayers, and not as floating neurospheres, enabled a thorough study of the phenotypic changes that occurred during their differentiation. Herein, we evaluated GSC-ECLs' behavior toward differentiating conditions by depriving them of growth factors and/or by adding BMP4 at different concentrations. After analyzing cellular morphology, proliferation and lineage marker expression, we determined that GSC-ECLs have distinct preferences in lineage choice, where some of them showed an astrocyte fate commitment and others a neuronal one. We found that this election seems to be dictated by the expression pattern of BMP signaling components present in each GSC-ECL. Additionally, treatment of GSC-ECLs with the BMP antagonist, Noggin, also led to evident phenotypic changes. Interestingly, under certain conditions, some GSC-ECLs adopted an unexpected smooth muscle-like phenotype. As a whole, our findings illustrate the wide differentiation potential of GSCs, highlighting their molecular complexity and paving a way to facilitate personalized differentiating therapies.


Assuntos
Proteína Morfogenética Óssea 4/metabolismo , Neoplasias Encefálicas/patologia , Proteínas de Transporte/metabolismo , Glioma/patologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Idoso , Antígenos CD/metabolismo , Proteína Morfogenética Óssea 4/farmacologia , Proteínas de Transporte/farmacologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/farmacologia , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Células Tumorais Cultivadas/patologia , Células Tumorais Cultivadas/fisiologia
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