RESUMO
BACKGROUND/AIMS: Jumping translocations are rare cytogenetic aberrations in haematological malignancies, the pathogenesis of which remains to be fully characterised. We investigated the mechanism of formation of jumping translocations in a case of adult common acute lymphoblastic leukaemia (ALL) positive for the Ph translocation. METHODS: Interphase and metaphase fluorescence in situ hybridisation (FISH) was performed using several probe systems. Results were correlated with findings on conventional cytogenetics. Granulocytes, T-cells and leukaemic B-cells in peripheral blood were sorted by immunomagnetic method and the terminal restriction fragment (TRF) length of these cellular populations was determined by Southern blot analysis. RESULTS: Duplicated BCR-ABL fusion signals were found on a dic(14;22)der(22)t(9;22) chromosome. Clonal jumping translocations, existing as evolutionary changes, involved the donor chromosomal segment distal to 1q12 jumping onto the telomere ends of 11q, 15p, 19p and 20p. Telomere length was decreased in the neoplastic B-cell population and contributed to the formation of the dicentric chromosome that showed absence of telomere repeats at fusion ends. Subsequent pericentromeric heterochromatin decondensation of chromosome 1q occurred, and this donor segment was randomly fused to the shortened telomere ends of non-homologous chromosomes. CONCLUSIONS: Both telomere shortening and pericentromeric heterochromatin decondensation contribute to the formation of jumping translocations, which is most probably a multi-stage process.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 22/genética , Cromossomos Humanos Par 9/genética , Análise Citogenética/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Translocação Genética/genética , Antígenos CD/biossíntese , Antígenos de Diferenciação Mielomonocítica/biossíntese , Southern Blotting , Evolução Fatal , Proteínas de Fusão bcr-abl/genética , Humanos , Hibridização in Situ Fluorescente/métodos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Fragmento de Restrição , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Sensibilidade e Especificidade , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico , Transdução de Sinais/genética , Telômero/genéticaRESUMO
BACKGROUND AND OBJECTIVES: The para-Bombay phenotype (also known as H-deficient secretor) is characterized by a lack of ABH antigens on red cells, but ABH substances are found in saliva. Molecular genetic analysis was performed for five Chinese individuals serologically typed as para-Bombay. MATERIALS AND METHODS: ABO genotyping and mutational analysis of both FUT1 (or H) and FUT2 (or Se) loci were performed for these individuals using the polymerase chain reaction, single-strand conformation polymorphism analysis and direct DNA sequencing. RESULTS: The ABO genotypes of these para-Bombay individuals correlated with the types of ABH substances found in the saliva. Their FUT1 genotypes were h1h2 (three individuals), h2h2 (one individual) and h2h6 (one individual). Alleles h1 (547-552delAG) and h2 (880-882delTT) were known frameshift mutations, while h6 (522C > A) was a missense mutation (Phe174Leu) not previously reported. These three mutations were rare sequence variations, each with an allele frequency of less than 0.005. Phe174 might be functionally important because this residue is conserved from mouse to human. Their FUT2 genotypes were Se357se357,385 for the h2h6 individual and Se357Se357) for the others. Both FUT2 alleles were known: one functional (Se357) and one weakly functional (se357,385). That they carried at least one copy of a functional FUT2 allele was consistent with their secretor status. As FUT1 and FUT2 are adjacent on 19q13.3, there are three possible haplotypes in these para-Bombay individuals: h1-Se357; h2-Se357; and h6-se357,385. CONCLUSIONS: A novel non-functional FUT1 allele (522C > A, or Phe174Leu) was identified in a para-Bombay individual and on a se357,385 haplotype background.
