RESUMO
T-cell receptor gene beta (TCRß) gene rearrangement represents a complex, tightly regulated molecular mechanism involving excision, deletion and recombination of DNA during T-cell development. RUNX1, a well-known transcription factor for T-cell differentiation, has recently been described to act in addition as a recombinase cofactor for TCRδ gene rearrangements. In this work we employed a RUNX1 knock-out mouse model and demonstrate by deep TCRß sequencing, immunostaining and chromatin immunoprecipitation that RUNX1 binds to the initiation site of TCRß rearrangement and its homozygous inactivation induces severe structural changes of the rearranged TCRß gene, whereas heterozygous inactivation has almost no impact. To compare the mouse model results to the situation in Acute Lymphoblastic Leukemia (ALL) we analyzed TCRß gene rearrangements in T-ALL samples harboring heterozygous Runx1 mutations. Comparable to the Runx1+/- mouse model, heterozygous Runx1 mutations in T-ALL patients displayed no detectable impact on TCRß rearrangements. Furthermore, we reanalyzed published sequence data from recurrent deletion borders of ALL patients carrying an ETV6-RUNX1 translocation. RUNX1 motifs were significantly overrepresented at the deletion ends arguing for a role of RUNX1 in the deletion mechanism. Collectively, our data imply a role of RUNX1 as recombinase cofactor for both physiological and aberrant deletions.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Deleção de Genes , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Proteínas Proto-Oncogênicas c-ets/genética , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Proteínas Repressoras/genética , Animais , Linfócitos B , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Contagem de Linfócitos , Camundongos Knockout , Linfócitos T , Timo/patologia , Variante 6 da Proteína do Fator de Translocação ETSAssuntos
Calosidades/diagnóstico por imagem , Fluordesoxiglucose F18 , Neoplasias Pulmonares/diagnóstico por imagem , Silicose/diagnóstico por imagem , Tomografia Computadorizada de Emissão , Diagnóstico Diferencial , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Compostos RadiofarmacêuticosAssuntos
Veia Axilar , Epônimos , Veia Subclávia , Trombose Venosa/história , Áustria , Inglaterra , História do Século XIX , Humanos , SíndromeRESUMO
We report the case of a 29-year-old man without immunodeficiency who acquired Pseudomonas aeruginosa pneumonia complicated by pulmonary abscess. The source of infection could be identified as aerosolized metalworking fluid at his workplace contaminated with Pseudomonas aeruginosa. A high titer of specific IgG antibodies (type-III-sensitization, Gell & Coombs) against Pseudomonas aeruginosa has been identified in the patients serum as an indicator for longstanding occupational airborne exposure to contaminated metalworking fluid. This community-acquired pneumonia has been reported to the industrial injuries insurance as an occupational disease for discussion of legal consequences and development of effective measures of prevention.
