RESUMO
Acute lymphoblastic leukemia (ALL) accounts for approximately 80% of all acute leukemias during childhood. Chromosomal anomalies resulting from gene fusion, which are frequent in leukemias, create hybrid transcripts, the great majority of which encode transcription factors. We analyzed 88 pediatric patients (median age 7.3 years) who had B-lineage acute lymphoblastic leukemia (B-ALL), using reverse transcriptase-polymerase chain reaction, to look for gene fusion transcripts of TEL/AML1, E2A/PBX1, BCR/ABL p190, and MLL/AF4. The frequencies of these transcripts were 21.21, 9.68, 3.03, and 0%, respectively. All positive cases had a common B-ALL immunophenotype. The low frequency of the TEL/AML1 transcript that is found in developing countries, such as Brazil, may be due to the low incidence of leukemia; this would support Greaves' hypothesis.
Assuntos
Aberrações Cromossômicas , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Brasil , Linhagem da Célula , Criança , Bases de Dados Genéticas , Feminino , Humanos , Imunofenotipagem , Masculino , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismoRESUMO
Infant acute leukemia (IAL) frequently involves breakage and recombination of the MLL gene with one of several potential partner genes. These gene fusions arise in utero and are similar to those found in leukemias secondary to chemotherapy with inhibitors of topoisomerase II (topo-II). This has led to the hypothesis that in utero exposures to chemicals may cause IAL via an effect on topo-II. We report a pilot case-control study of IAL across different countries and ethnic groups. Cases (n = 136) were population-based in most centers. Controls (n = 266) were selected from inpatients and outpatients at hospitals serving the same populations. MLL rearrangement status was derived by Southern blot analysis, and maternal exposure data were obtained by interviews using a structured questionnaire. Apart from the use of cigarettes and alcohol, very few mothers reported exposure to known topo-II inhibitors. Significant case-control differences were apparent for ingestion of several groups of drugs, including herbal medicines and drugs classified as "DNA-damaging," and for exposure to pesticides with the last two being largely attributable, respectively, to one nonsteroidal anti-inflammatory drug, dipyrone, and mosquitocidals (including Baygon). Elevated odds ratios were observed for MLL+ve (but not MLL-ve) leukemias (2.31 for DNA-damaging drugs, P = 0.03; 5.84 for dipyrone, P = 0.001; and 9.68 for mosquitocidals, P = 0.003). Although it is unclear at present whether these particular exposures operate via an effect on topo-II, the data suggest that specific chemical exposures of the fetus during pregnancy may cause MLL gene fusions. Given the widespread use of dipyrone, Baygon, and other carbamate-based insecticides in certain settings, confirmation of these apparent associations is urgently required.
Assuntos
Proteínas de Ligação a DNA/genética , Inibidores Enzimáticos/efeitos adversos , Leucemia Mieloide/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/induzido quimicamente , Efeitos Tardios da Exposição Pré-Natal , Proto-Oncogenes , Inibidores da Topoisomerase II , Fatores de Transcrição , Doença Aguda , Fusão Gênica Artificial , Estudos de Casos e Controles , Inibidores Enzimáticos/farmacocinética , Feminino , Histona-Lisina N-Metiltransferase , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide/genética , Masculino , Troca Materno-Fetal , Proteína de Leucina Linfoide-Mieloide , Projetos Piloto , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Gravidez , Fatores de RiscoRESUMO
We analysed 67 samples from Brazilian children of diverse ethnic origins with acute lymphoblastic leukaemia (ALL) for the presence of the TEL-AML1 fusion gene transcripts using reverse transcription polymerase chain reaction (RT-PCR). All 12 positive cases (20% of the 60 B-cell precursor ALL) had common (CD10+) ALL with a mean age of 4 years (range 1-10 years). We conclude that the frequency, age, distribution and clinical features of the TEL-AML1 fusion gene-positive ALL is similar in the diverse ethnic backgrounds of the Brazilian children to that in other countries with predominantly white Caucasian or oriental ethnicity. Apparent exceptions to this generality are discussed.
Assuntos
Linfoma de Burkitt/genética , Frequência do Gene , Leucemia-Linfoma de Células T do Adulto/genética , Proteínas de Fusão Oncogênica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , População Negra , Brasil , Linfoma de Burkitt/etnologia , Criança , Pré-Escolar , Subunidade alfa 2 de Fator de Ligação ao Core , Feminino , Humanos , Lactente , Leucemia-Linfoma de Células T do Adulto/etnologia , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/etnologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , População BrancaRESUMO
We have examined DNA from fifteen unrelated pyruvate kinase deficient patients with hereditary nonspherocytic hemolytic anemia (HNSHA) for the molecular alterations responsible for the enzyme deficiency. All but 3 of the 30 putative mutations were identified. Fourteen different mutations were found. Nine were missense mutations: 320 T-->C, 823 G-->C, 1276 C-->T, 1378 G-->A, 1484 C-->T, 1529 G-->A, 1654 G-->A, 1675 C-->G; three were nonsense mutations: 603 G-->A, 721 G-->T, 1501 C-->T; one was an insertion at 1574 GGG-->GGGG and the other a three nucleotide in-frame deletion 391-392-393 ATC. Eight of these mutations have not been previously described. We also investigated all of the patients for the C/A polymorphism at nt 1705 and the microsatellite ATT repeat in intron 11. All of the mutations that had previously been reported by us (391-393del, 721T, 1484T, 1529A) were found in the context of the same haplotype as the earlier cases, supporting the concept that each may have a single origin.
