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1.
J Clin Immunol ; 33(6): 1088-99, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23708964

RESUMO

PURPOSE: This study reports the identification of a novel heterozygous IKBA missense mutation (p.M37K) in a boy presenting with ectodermal dysplasia with immunodeficiency (EDA-ID) who had wild type IKBKG gene encoding NEMO. Our aim was to characterize the clinical course of this IκB-α gain-of-function mutant and to investigate if the p.M37K substitution affects NF-κB activation by interfering with IκB-α degradation, thus impairing NF-κB signaling and causing the EDA-ID phenotype. METHODS: NF-κB signaling was evaluated by measuring IκB-α degradation in patient fibroblasts. In addition, transiently transfected HeLa cells expressing either the M37K-mutant IκB-α allele, the previously characterized S36A-mutant IκB-α allele, or wild type IκB-α were evaluated for IκB-α degradation and NF-κB nuclear translocation following stimulation with TNF-α. RESULTS: Clinical findings revealed a classical ectodermal dysplasia phenotype complicated by recurrent mucocutaneous candidiasis, hypothyroidism, hypopituitarism, and profound combined immunodeficiency with decreased numbers of IL-17 T cells. IκB-α degradation after TNF-α and TLR agonist stimulation was abolished in patient fibroblasts as well as in HeLa cells expressing M37K-IκB-α similar to cells expressing S36A-IκB-α resulting in impaired nuclear translocation of NF-κB and reduced NF-κB dependent luciferase activity compared to cells expressing wild type IκB-α. Patient whole blood cells failed to secrete IL-6 in response to IL-1ß, Pam2CSK4, showed reduced responses to LPS and PMA/Ionomycin, and lacked IL-10 production in response to TNF-α. CONCLUSION: The novel heterozygous mutation p.M37K in IκB-α impairs NF-κB activation causing autosomal dominant EDA-ID with an expanded clinical phenotype.


Assuntos
Núcleo Celular/metabolismo , Displasia Ectodérmica/imunologia , Fibroblastos/imunologia , Quinase I-kappa B/metabolismo , Síndromes de Imunodeficiência/imunologia , Poliendocrinopatias Autoimunes/imunologia , Transporte Ativo do Núcleo Celular/genética , Pré-Escolar , Citocinas/imunologia , Células HeLa , Humanos , Quinase I-kappa B/genética , Lactente , Ativação Linfocitária/genética , Masculino , Mutação de Sentido Incorreto/genética , Proteólise , Células Th17/imunologia , Transgenes/genética
2.
Cancer Genet Cytogenet ; 166(2): 146-51, 2006 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-16631471

RESUMO

Mutations in the gene coding for the alpha-subunit of the heterotrimeric stimulatory G protein Gs are the most frequently identified molecular events in the development of somatotroph adenomas in adults. In children and adolescents, somatotroph adenomas are rare, and only two cases with the Gs alpha mutation have been reported so far. In this study, we therefore investigated the prevalence of activating Gs alpha mutations in 17 patients younger than 20 years with pituitary growth hormone-secreting adenomas and examined the characteristics of mutation-positive cases. The most common C-->T substitution in codon 201 was detected in two children. Interestingly, in contrast to the remaining cases, the adenomas positive for the Gs alpha mutation proved to be nonsporadic, but part of a syndrome associated with endocrine tumors in both individuals. Additional tests confirmed McCune-Albright syndrome in the first patient and multiple endocrine neoplasia type 1 syndrome in the second patient. In contrast to the findings in adult cases, somatotroph adenomas in young patients seem to carry somatic Gs alpha mutations at a lower frequency, and germ-line or early postzygotic mutational events may be responsible for the shortened latency of tumorigenesis.


Assuntos
Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Adenoma Hipofisário Secretor de Hormônio do Crescimento/genética , Mutação/genética , Adolescente , Adulto , Distribuição por Idade , Criança , Éxons/genética , Feminino , Humanos , Masculino , Mapeamento por Restrição
3.
World J Gastroenterol ; 12(37): 6054-8, 2006 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-17009409

RESUMO

AIM: To study the expression of HBV enhancer II by transcription factor COUP-TF1. METHODS: In order to study the regulation of HBV variants in the vicinity of the NRRE we cloned luciferase constructs containing the HBV enhancer II from variants and from HBV genotypes A and D and cotransfected them together with expression vectors for COUP-TF1 into HepG2 cells. RESULTS: Our findings show that enhancer II of HBV genotype A is also repressed by COUP-TF1. In contrast, two different enhancer II constructs of HBV genotype D were activated by COUP-TF1. The activation was independent of the NRRE because a natural variant with a deletion of nt 1763-1770 was still activated by COUP-TF1. CONCLUSION: Regulation of transcription of the HBV genome seems to differ among HBV genomes derived from different genotypes. These differences in transcriptional control among HBV genotypes may be the molecular basis for differences in the clinical course among HBV genotypes.


Assuntos
Fator I de Transcrição COUP/genética , Elementos Facilitadores Genéticos/genética , Regulação Viral da Expressão Gênica/genética , Vírus da Hepatite B/genética , Sequência de Bases , Linhagem Celular Tumoral , DNA Viral/genética , Ensaio de Desvio de Mobilidade Eletroforética , Deleção de Genes , Genótipo , Humanos , Dados de Sequência Molecular , Transfecção
4.
J Clin Virol ; 29(1): 39-43, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-14675868

RESUMO

Eight genotypes (A-H) of hepatitis B virus (HBV) are known with variations in nucleotide sequences greater than 8%. Several recent publications found that the clinical course and outcome of antiviral therapy depended on the genotype of the infecting HBV strain. Large epidemiological studies will require the availability of a system which is rapid, reliable and can be performed on a large number of samples. We have developed a multiplex-PCR assay which uses genotype-specific primer pairs for HBV genotypes A-F. These primer pairs specifically amplified HBV DNA of the respective genotype, either in single or in multiplex-PCR. Sensitivity of the assay was in the range of 10(4) genome equivalents.


Assuntos
Primers do DNA , Vírus da Hepatite B/classificação , Vírus da Hepatite B/isolamento & purificação , Reação em Cadeia da Polimerase/métodos , DNA Viral/análise , Genótipo , Hepatite B/epidemiologia , Hepatite B/virologia , Vírus da Hepatite B/genética , Humanos , Sensibilidade e Especificidade , Especificidade da Espécie
5.
Haematologica ; 89(12): 1492-7, 2004 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-15590400

RESUMO

BACKGROUND AND OBJECTIVES: NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that protects cells against mutagenicity from free radicals and toxic oxygen metabolites. The gene coding for NQO1 is subject to a genetic polymorphism at nucleotide position 609 (C-->T) of the human NQO1 cDNA. Heterozygous individuals (C/T) have intermediate activity and homozygotes for the variant allele (T/T) are deficient in NQO1 activity. In previous studies, genotypes conferring lower NQO1 activity have been associated with an increased risk of acute leukemia, particularly infant leukemia carrying MLL/AF4 fusion genes. In the present study, we investigated this association in our population and extended the analysis to other subgroups of pediatric hematologic neoplasms characterized by specific fusion genes. DESIGN AND METHODS: We genotyped 138 patients with childhood acute lymphoblastic leukemia (ALL) carrying distinct fusion genes (MLL/AF4=35; BCR/ABL=31; TEL/AML1=72), 71 cases of pediatric sporadic Burkitt's lymphoma and 190 healthy control individuals for the NQO1 C609T polymorphism. RESULTS: When compared to the healthy control group, only children with Burkitt's lymphoma significantly more often had NQO1 genotypes associated with lower NQO1 activity (odds ratio, 1.81; p=0.036), predominantly at a younger age (< 9 years at diagnosis: odds ratio, 3.02; p=0.003). INTERPRETATION AND CONCLUSIONS: Our results suggest that in our population the NQO1 C609T polymorphism does not confer an increased risk of the investigated entities of childhood ALL. However, there may be a modulating role for NQO1 in the pathogenesis of pediatric sporadic Burkitt's lymphoma.


Assuntos
Linfoma de Burkitt/genética , NAD(P)H Desidrogenase (Quinona)/genética , Polimorfismo de Nucleotídeo Único , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Adolescente , Adulto , Fatores Etários , Idoso , Linfoma de Burkitt/enzimologia , Transformação Celular Neoplásica/induzido quimicamente , Transformação Celular Neoplásica/genética , Criança , Pré-Escolar , Códon/genética , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Feminino , Proteínas de Fusão bcr-abl/genética , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Proteína de Leucina Linfoide-Mieloide/genética , NAD(P)H Desidrogenase (Quinona)/fisiologia , Proteínas de Fusão Oncogênica/genética , Praguicidas/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/enzimologia , Risco
6.
Eur J Obstet Gynecol Reprod Biol ; 101(1): 47-53, 2002 Feb 10.
Artigo em Inglês | MEDLINE | ID: mdl-11905404

RESUMO

OBJECTIVE: The human placenta expresses a variety of vasoactive substances and neuropeptides, which play an important role in the regulation of placental blood flow in both the maternal and foetal compartment and are therefore of critical importance for foetal growth and development. Our study was planned to examine placental mRNA amounts of vasodilatory adrenomedullin (AM), calcitonin gene-related peptide (CGRP) and their receptors (AM-R and CGRP-R) in preeclampsia and HELLP syndrome (hemolysis, elevated liver enzymes, low platelets). These are severe maternal conditions leading to an altered uteroplacental and fetoplacental perfusion and a higher risk for foetal growth retardation, premature delivery, infant mortality, and even maternal death. STUDY DESIGN: We included 17 patients with preeclampsia, four women with HELLP syndrome and 34 controls. After delivery, the mRNA levels of AM, AM-R, CGRP, CGRP-R, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and -actin were measured in placental villi and chorionic plates using quantitative real-time PCR. RESULTS: AM/-actin and AM/GAPDH mRNA ratios were significantly lower in placental villi in preeclampsia than in controls (P<0.05) as were CGRP/-actin and CGRP/GAPDH mRNA ratios in chorionic plates (P<0.05). Placental AM-R and CGRP-R mRNA amounts were unaffected. CONCLUSION: Our data show a reduction of AM and CGRP mRNAs in contrast to unchanged mRNA levels of their receptors in placenta specimens of women with preeclampsia or HELLP syndrome.


Assuntos
Peptídeo Relacionado com Gene de Calcitonina/genética , Síndrome HELLP/metabolismo , Peptídeos/genética , Placenta/metabolismo , Pré-Eclâmpsia/metabolismo , Actinas/genética , Adrenomedulina , Adulto , Feminino , Expressão Gênica , Gliceraldeído-3-Fosfato Desidrogenases/genética , Humanos , Reação em Cadeia da Polimerase , Gravidez , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Adrenomedulina , Receptores de Peptídeo Relacionado com o Gene de Calcitonina/genética , Receptores de Peptídeos/genética , Análise de Regressão
7.
Pharmacology ; 69(2): 74-8, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-12928580

RESUMO

The hypoxia-inducible factor 1alpha (HIF-1alpha), a member of the PAS superfamily, is a global regulator of cellular and systemic O(2) homeostasis as well as embryonic development. As the activity of HIF-1alpha is increased by a lowered oxygen tension in vivo and in vitro, we established a cell line producing high amounts of HIF-1alpha under normoxic conditions. As this overexpression was inducible by doxycycline, we can now provide a system to study HIF-1alpha-dependent gene regulation under normoxic as well as hypoxic conditions. We were able to show that the doxycycline-induced induction of the target gene HIF-1alpha--followed by the message of its target genes erythropoietin and vascular endothelial growth factor--is a dose- and time-dependent process. As the inducible overexpression of HIF-1alpha did not increase the rate of apoptosis, it provides a helpful new tool in drug discovery and tumor research to differentiate between hypoxia-dependent and hypoxia-independent pathways during HIF-1alpha-dependent gene regulation and HIF-1alpha-dependent effects on apoptosis.


Assuntos
Apoptose/genética , Hipóxia/genética , Fatores de Transcrição/genética , Células Cultivadas , Regulação da Expressão Gênica , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia , Fatores de Transcrição/fisiologia
8.
J Hepatol ; 37(6): 855-62, 2002 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-12445429

RESUMO

BACKGROUND/AIMS: Epidemiological studies have shown that coinfection or superinfection with hepatitis B virus (HBV) and C virus (HCV) frequently leads to the suppression of hepatitis B virus replication. The mechanism of this phenomenon is still unclear. Shih et al. [J Virol 1993;67:5823] reported a direct suppression of HBV replication by the core protein of HCV. The target structure of HCV core protein in this system remained unclear. METHODS: As HCV core protein has been shown to influence expression from transcriptional elements, we studied whether HCV core protein altered the activity of the two HBV enhancers 1 and 2. Luciferase vectors for HBV enhancers 1 or 2 were cotransfected with expression constructs for HCV core protein in murine and human hepatocyte lines. RESULTS: Full-length HCV core protein suppressed the HBV enhancer 1 up to 11-fold, the enhancer 2 3-4-fold. Suppression of HBV enhancer 1 by HCV core from genotype 1b was stronger than by HCV core of genotypes 3a or 1a. Carboxyterminally truncated core proteins had lower or no suppression activity. CONCLUSIONS: These data suggest that HCV core protein may directly repress transcription of the HBV RNAs. This trans-repression may contribute to suppression of HBV replication in patients coinfected with both viruses.


Assuntos
Elementos Facilitadores Genéticos/efeitos dos fármacos , Vírus da Hepatite B/genética , Vírus da Hepatite B/metabolismo , Proteínas do Core Viral/farmacologia , Animais , Linhagem Celular , Genótipo , Hepatócitos/metabolismo , Humanos , Camundongos , Fragmentos de Peptídeos/farmacologia , Células Tumorais Cultivadas , Proteínas do Core Viral/química
9.
Kidney Int ; 61(5): 1707-13, 2002 May.
Artigo em Inglês | MEDLINE | ID: mdl-11967020

RESUMO

BACKGROUND: Adrenomedullin (ADM) exerts antiproliferative effects on rat mesangial cells in vitro and, therefore is a possible renoprotective agent. In contrast, nitric oxide (NO) is capable of exerting both cytoprotective and cytotoxic actions. It was the objective of the present study to examine whether NO stimulates the ADM system. METHODS: Rat mesangial cells were incubated with the NO donors GSNO and SNAP, the guanylate cyclase inhibitor ODQ, and the cGMP analog 8-bromo-cGMP. ADM radioligand binding, ADM-induced intracellular cAMP-accumulation (radioimmunoassay) and ADM receptor gene expression (TaqMan real time PCR) were measured. RESULTS: Twenty-four hour treatment of mesangial cells with GSNO and SNAP (100 micromol/L each) increased the maximal binding of ADM to its receptor from 52%+/- 4% to 101%+/- 4% (P < 0.001) and 81%+/- 2% (P < 0.001), respectively. GSNO, SNAP (both 100 micromol/L) and 8-bromo-cGMP (50 micromol/L) increased EC50 from 9.9 x 10-8 to 7.0 x 10-10, 4.8 x 10-10, 1.1 x 10-9, respectively. In contrast, combined pretreatment with GSNO (100 micromol/L) and ODQ (100 micromol/L) reduced EC50 to values similar to the control cells (2.4 x 10-8). In contrast, ADM receptor gene expression was reduced significantly by different concentrations of GSNO, SNAP, and by 50 micromol/L 8-bromo-cGMP, but not by 8-bromo-cAMP. CONCLUSIONS: NO increases ADM signal transduction via a cGMP dependent pathway. This effect is caused, at least in part, by an increase in ADM receptor availability and is counteracted in a feedback manner on the mRNA level. This mechanism might direct the impact of NO on mesangial cell function toward cytoprotection.


Assuntos
Mesângio Glomerular/metabolismo , Óxido Nítrico/metabolismo , Receptores de Peptídeos/genética , Receptores de Peptídeos/metabolismo , Animais , Divisão Celular/fisiologia , Células Cultivadas , AMP Cíclico/metabolismo , Citoproteção/fisiologia , Fragmentação do DNA , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/fisiologia , Mesângio Glomerular/citologia , L-Lactato Desidrogenase/metabolismo , Doadores de Óxido Nítrico/farmacologia , RNA Mensageiro/análise , Ensaio Radioligante , Ratos , Receptores de Adrenomedulina , Transdução de Sinais/fisiologia , Timidina/farmacocinética , Trítio
10.
J Pediatr Hematol Oncol ; 25(12): 948-51, 2003 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-14663277

RESUMO

OBJECTIVE: Pearson bone marrow-pancreas syndrome (PS) is a rare, usually fatal mitochondrial disorder involving the hematopoietic system in early infancy. Due to the diversity of clinical symptoms, the diagnosis can be difficult. The authors describe a boy with severe hypoplastic anemia in whom extensive clinical, biochemical, and morphologic findings led to the diagnosis of PS, and molecular analysis revealed a novel deletion of mitochondrial DNA from nucleotide position 10.371 to 14.607. METHODS: The patient is a 2-year-old boy who presented at age 5 months with hypoplastic macrocytic anemia. His first months of life and the family history were uneventful. Extensive pretransfusion evaluations did not reveal a metabolic, infectious, or hematologic-neoplastic etiology, and he had no evidence of exocrine pancreatic insufficiency. However, a second bone marrow aspirate at age 7 months showed a reduced cell number, vacuolated erythroblasts and myeloblasts, and ringed sideroblasts, so PS was suspected. RESULTS: Additional molecular analysis from the boy's blood leukocytes revealed a deletion of mitochondrial DNA from nucleotide position 10.371 to 14.607, which was absent in his mother's blood cells, consistent with a sporadic mutation as commonly seen in PS. The muscle histology and the respiratory chain enzymes were normal. CONCLUSIONS: Mitochondriopathies should be considered in children with persistent non-neuromuscular symptoms such as unexplained refractory anemia. Due to the often-fatal course of PS, the rapid detection of mitochondrial DNA deletions is imperative for diagnosis and family counseling.


Assuntos
DNA Mitocondrial/genética , Deleção de Genes , Doenças Mitocondriais/genética , Anemia Macrocítica/genética , Anemia Macrocítica/patologia , Doenças da Medula Óssea/genética , Doenças da Medula Óssea/patologia , Exame de Medula Óssea , Pré-Escolar , Análise Mutacional de DNA , Humanos , Masculino , Doenças Mitocondriais/patologia , Doenças Mitocondriais/terapia , Pancreatopatias/genética , Pancreatopatias/patologia , Síndrome
11.
Blood ; 101(9): 3635-40, 2003 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-12506024

RESUMO

TEL/AML1-positive childhood acute lymphoblastic leukemias (ALLs) generally have low-risk features, but still about 20% of patients relapse. Our initial molecular genetic analyses in 2 off-treatment relapses suggested that the initial and relapse clones represent different subclones that evolved from a common TEL/AML1-positive, treatment-resistant precursor. In order to further elaborate on this hypothesis, we studied 2 patients with late systemic relapses of their TEL/AML1-positive ALL (41 months and 49 months after initial diagnosis, respectively) who had distinct clonal antigen receptor gene rearrangements at diagnosis and relapse. These clone-specific markers enabled us to determine the responsiveness of the individual clones to treatment. The matching genomic TEL/AML1 breakpoints of the initial and the relapse clones in these patients confirmed their origin from a common progenitor cell. This proof was especially important in one of these 2 leukemias without a common antigen receptor gene rearrangement. Our retrospective analysis revealed that in both cases the relapse clone was already present at diagnosis. Despite their small sizes (5 x 10(-3) and 1 x 10(-4), respectively), we were able to detect their much slower responses to therapy compared with the dominant leukemic clone. Moreover, in all instances, these initially slow-responding clones, after they had developed into the relapse leukemia, were rapidly eradicated by the relapse treatment, underlining their different biology at the 2 time points of leukemia manifestation. We thus hypothesize that the minor clone was not fully malignant at initial diagnosis but acquired further mutations that may be necessary for the manifestation of relapse.


Assuntos
Biomarcadores Tumorais/genética , Cromossomos Humanos Par 12/ultraestrutura , Cromossomos Humanos Par 21/ultraestrutura , Proteínas de Neoplasias/genética , Células-Tronco Neoplásicas/patologia , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Pré-Leucemia/patologia , Translocação Genética , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Sobrevivência Celular , Pré-Escolar , Células Clonais/patologia , Subunidade alfa 2 de Fator de Ligação ao Core , Feminino , Rearranjo Gênico do Linfócito B , Humanos , Hibridização in Situ Fluorescente , Lactente , Masculino , Proteínas de Neoplasias/análise , Proteínas de Fusão Oncogênica/análise , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Pré-Leucemia/genética , Recidiva , Indução de Remissão , Estudos Retrospectivos , Fatores de Tempo
12.
Genes Chromosomes Cancer ; 36(4): 393-401, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12619163

RESUMO

The translocation t(9;11)(p22;q23) is a recurring chromosomal abnormality in acute myeloid leukemia (AML) fusing two genes designated as MLL and AF9. Within MLL, almost all rearrangements cluster in an 8.3-kb restricted region and fuse 5' portions of MLL to a variety of heterologous genes in various 11q23 translocations. AF9 is one of the most common fusion partners of MLL. It spans more than 100 kb, and two breakpoint cluster regions (BCRs) have been identified in a telomeric region of intron 4 (BCR1) and within introns 7 and 8 (BCR2). We investigated 11 children's bone marrow or peripheral blood samples (3 AML, 5 t-AML, 2 ALL, 1 ALL relapse) and two cell lines (THP-1 and Mono-Mac-6) with cytogenetically diagnosed translocations t(9;11). By use of an optimized multiplex nested long-range PCR assay, a breakpoint-spanning DNA fragment from each sample was amplified and directly sequenced. In four patients and two cell lines, the AF9 breakpoints were located within BCR1 and in two patients within BCR2, respectively. However, in five patients the AF9 breakpoints were found outside the previously described BCRs within the centromeric region of intron 4 and even within intron 3 in one case. All five patients with a secondary AML, who had not received etoposides during treatment of the primary malignant disease, revealed almost identical MLL breakpoints very close to a breakage hot spot inducible by topoisomerase II inhibitors or apoptotic triggers in vitro. Sequence patterns around the breakpoints indicated involvement of a "damage-repair mechanism" in the development of t(9;11) similar to t(4;11) in infants' acute leukemia.


Assuntos
Quebra Cromossômica/genética , Cromossomos Humanos Par 11/genética , Cromossomos Humanos Par 9/genética , Proteínas de Ligação a DNA/genética , Etoposídeo/uso terapêutico , Leucemia Mieloide/induzido quimicamente , Leucemia Mieloide/genética , Segunda Neoplasia Primária/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proto-Oncogenes , Fatores de Transcrição , Doença Aguda , Adolescente , Sequência de Aminoácidos , Criança , Pré-Escolar , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Masculino , Dados de Sequência Molecular , Proteína de Leucina Linfoide-Mieloide , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/genética , Proteínas Nucleares/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Células Tumorais Cultivadas
13.
Genes Chromosomes Cancer ; 41(3): 291-6, 2004 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-15334554

RESUMO

Therapy-related acute myeloid leukemia (t-AML) characterized by the t(9;11)(p22;q23) translocation is one of the most frequent secondary malignancies. The timing of the initiation of translocation and of development of the malignant t(9;11) clone during chemotherapy is presently unknown. In the present study, we backtracked bone marrow samples from three children during treatment for acute lymphoblastic leukemia (ALL). Two patients developed a t(9;11)-positive t-AML 19 and 30 months after therapy start, whereas the third patient, diagnosed with a rare t(9;11)-positive ALL, suffered from an ALL relapse 23 months after initial diagnosis. The genomic MLL-MLLT3 (MLL-AF9) fusion site was amplified by a multiplex, nested long-range PCR and used as a clonal marker for quantification of the MLL-MLLT3-positive cells during chemotherapy. The t(9;11)-positive clone was detectable 13 and 18 months after therapy start in both t-AML cases, which was 6-12 months before clinical diagnosis of the secondary malignancy. In the t(9;11)-positive ALL patient, the identical leukemic clone reoccurred during maintenance therapy after a short molecular remission, 8 months before clinically overt ALL relapse. The time course and characteristics of the genomic breakpoints in the present t-AML cases support the hypothesis of translocation formation as a result of defective breakage repair after topoisomerase II cleavage.


Assuntos
Cromossomos Humanos Par 11/ultraestrutura , Cromossomos Humanos Par 9/ultraestrutura , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Criança , Pré-Escolar , DNA Topoisomerases Tipo II/metabolismo , Feminino , Humanos , Lactente , Masculino , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Translocação Genética
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