Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 2 de 2
Filtrar
1.
Sci Rep ; 10(1): 10024, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32572036

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 ETS
2.
Leukemia ; 27(2): 305-14, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22751451

RESUMO

Constitutively activated FLT3 signaling is common in acute myeloid leukemia, and is currently under evaluation for targeted therapy, whereas little data is available in T-cell acute lymphoblastic leukemia (T-ALL). We analyzed 357 T-ALL cases for FLT3 mutations and transcript expression. FLT3 mutations (3% overall) and overexpression (FLT3 high expresser (FLT3(High))) were restricted to immature/TCRγδ T-ALLs. In vitro FLT3 inhibition induced apoptosis in only 30% of FLT3(High) T-ALLs and did not correlate with mutational status. In order to investigate the mechanisms of primary resistance to FLT3 inhibition, a broad quantitative screen for receptor kinome transcript deregulation was performed by Taqman Low Density Array. FLT3 deregulation was associated with overexpression of a network of receptor kinases (RKs), potentially responsible for redundancies and sporadic response to specific FLT3 inhibition. In keeping with this resistance to FLT3 inhibition could be reversed by dual inhibition of FLT3 and KIT with a synergistic effect. We conclude that immature T-ALL may benefit from multitargeted RK inhibition and that exploration of the receptor kinome defines a rational strategy for testing multitarget kinase inhibition in malignant diseases.


Assuntos
Apoptose/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Mutação/genética , Leucemia-Linfoma Linfoblástico de Células T Precursoras/enzimologia , Inibidores de Proteínas Quinases/farmacologia , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Tirosina Quinase 3 Semelhante a fms/antagonistas & inibidores , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , DNA de Neoplasias/genética , Sinergismo Farmacológico , Feminino , Citometria de Fluxo , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Prognóstico , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais , Taxa de Sobrevida , Células Tumorais Cultivadas , Adulto Jovem , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA