RESUMO
Based on cytogenetic studies, non-random chromosomal translocations which involve the HOX11 gene at locus 10q24 and the TCR genes at loci 7q35 or 14q11 have been reported to occur in 5% of T-ALL. HOX11, a member of the homeobox family of genes, has been shown to play a role in T-ALL. The activation of the HOX11 gene by translocations to the TCR locus results in the inappropriate expression of a 2.3 kb transcript. In this paper we describe a t(10;14)(q24;q11) breakpoint from a T-ALL patient specimen. The breakpoint appears to be mediated by errors in the TCR/V(D)J recombination system, but is more complex than commonly described reciprocal translocations between the HOX11 and TCR genes, since it involves an inversion event of the TCRdelta genes. In addition, the breakpoint was characterised to a previously unsequenced area of the 10q24 locus, 3.4 kb upstream of the HOX11 gene. This breakpoint is more centromeric than the breakpoint cluster region previously shown to be involved in the majority of reported t(10;14)(q24;q11) translocations. Hence, our investigations of the translocation breakpoint in this patient identify another breakpoint region in the 10q24 locus and may define a novel recombination 'hot spot'. Surprisingly, our studies provide a mechanism for a previously unexplained complex translocation described by another group which involves the same region of the HOX11 promoter.
Assuntos
Cromossomos Humanos Par 10 , Cromossomos Humanos Par 14 , Proteínas de Homeodomínio/genética , Leucemia-Linfoma de Células T do Adulto/genética , Proteínas Oncogênicas/genética , Translocação Genética , Sequência de Bases , Southern Blotting , Criança , DNA de Neoplasias/análise , Humanos , Masculino , Dados de Sequência Molecular , Proteínas Proto-Oncogênicas , Análise de Sequência , Homologia de Sequência do Ácido NucleicoRESUMO
Based on cytogenetic analysis, chromosomal translocations involving band 10q24 occur in 4-7% of T-cell acute lymphoblastic leukemia (T-ALL). The HOX11 gene is located in this chromosomal band and is activated by translocations t(10;14) (q24;q11) and t(7;10) (q35;q24). Ectopic expression of the HOX11 gene appears to be involved in the development of T-cell tumors. The aim of this study was to determine the frequency of HOX11 activation in pediatric ALL patients and to correlate gene expression with ALL immunophenotype. None of 53 B-lineage ALLs was positive for HOX11 expression, however, Northern blot and RT-PCR analysis revealed that four of 12 T-ALLs (33%) showed expression of the gene. In order to assess whether HOX11 expression is present in other pediatric malignancies we examined a panel of 20 tumor cell lines established from solid tumors and leukemias, but none of them showed expression of HOX11. Using our RT-PCR method we confirmed that HOX11 expression is not detectable in normal T-cells. These findings indicate that HOX11 expression in pediatric ALL is exclusive to T-ALL and does not occur in B-lineage ALL. The frequency detected by molecular techniques was significantly higher than the frequency reported in the literature based on cytogenetic analysis. These results support the notion that ectopic expression of the HOX11 homeobox gene is a crucial step in T-cell tumorigenesis.
Assuntos
Proteínas de Homeodomínio/genética , Proteínas Oncogênicas/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Linfócitos T/imunologia , Adolescente , Sequência de Bases , Northern Blotting , Células Cultivadas , Criança , Pré-Escolar , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 14 , Primers do DNA , Feminino , Humanos , Imunofenotipagem , Lactente , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células Precursoras/imunologia , Proteínas Proto-Oncogênicas , RNA Mensageiro/genética , Ativação Transcricional , Translocação Genética , Células Tumorais CultivadasRESUMO
Cell line PER-117 is a T-cell receptor negative human T-cell line that can be induced to express a functional interleukin-2 receptor (IL-2R). Recombinant interleukin-1 (IL-1) as well as certain combinations of inducer substances could be shown to stimulate the expression of the p55 (alpha)-chain of the IL-2R in PER-117 cells. The synergistic increases in IL-2R alpha expression were demonstrated at the cell surface as well as at the mRNA level. The results suggested that in PER-117 cells IL-1 appears to induce expression of the alpha-chain by pathways that are different to activation via protein kinase C (PKC), and that drug-induced cyclic AMP (cAMP) activation did not substitute for IL-1. We found that the regulation of mRNA for IL-2R beta (p75) differed significantly from that seen for IL-2R alpha. Moreover, the requirements for IL-2R alpha induction determined for this cell line differ from other human cell lines, which may reflect that there are distinct requirements for activation depending on the stage of differentiation and/or lineage of the cells. The PER-117 cell line provides a unique model to examine further the mechanism leading to induction of a functional IL-2R at an early stage of human T-cell differentiation.