RESUMEN
In T-cell acute lymphoblastic leukemia (T-ALL), transcription factors are known to be deregulated by chromosomal translocations, but mutations in protein tyrosine kinases have only rarely been identified. Here we describe the extrachromosomal (episomal) amplification of ABL1 in 5 of 90 (5.6%) individuals with T-ALL, an aberration that is not detectable by conventional cytogenetics. Molecular analyses delineated the amplicon as a 500-kb region from chromosome band 9q34, containing the oncogenes ABL1 and NUP214 (refs. 5,6). We identified a previously undescribed mechanism for activation of tyrosine kinases in cancer: the formation of episomes resulting in a fusion between NUP214 and ABL1. We detected the NUP214-ABL1 transcript in five individuals with the ABL1 amplification, in 5 of 85 (5.8%) additional individuals with T-ALL and in 3 of 22 T-ALL cell lines. The constitutively phosphorylated tyrosine kinase NUP214-ABL1 is sensitive to the tyrosine kinase inhibitor imatinib. The recurrent cryptic NUP214-ABL1 rearrangement is associated with increased HOX expression and deletion of CDKN2A, consistent with a multistep pathogenesis of T-ALL. NUP214-ABL1 expression defines a new subgroup of individuals with T-ALL who could benefit from treatment with imatinib.
Asunto(s)
Genes abl , Leucemia-Linfoma de Células T del Adulto/genética , Proteínas de Complejo Poro Nuclear/genética , Plásmidos/genética , Secuencia de Aminoácidos , Fusión Artificial Génica , Secuencia de Bases , Benzamidas , Línea Celular Tumoral , Cromosomas Humanos Par 9/genética , ADN de Neoplasias/genética , Inhibidores Enzimáticos/uso terapéutico , Amplificación de Genes , Humanos , Mesilato de Imatinib , Hibridación Fluorescente in Situ , Leucemia-Linfoma de Células T del Adulto/tratamiento farmacológico , Leucemia-Linfoma de Células T del Adulto/enzimología , Datos de Secuencia Molecular , Piperazinas/uso terapéutico , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Proteínas Tirosina Quinasas/genética , Pirimidinas/uso terapéuticoRESUMEN
We recently cloned the CHIC2 gene (previously BTL) by virtue of its involvement in a chromosomal translocation t(4;12)(q11;p13) occurring in acute myeloid leukemias. In this study we show that CHIC2 is a member of a highly conserved family of proteins characterized by the presence of a striking cysteine-rich hydrophobic (CHIC) motif. Our data illustrate that cysteines in this central CHIC motif are palmitoylated and that CHIC2 is associated with vesicular structures and the plasma membrane. The CHIC proteins thus resemble the cysteine string proteins, which function in regulated exocytosis.
