RESUMEN
Growing evidence links abnormal epigenetic control to the development of hematological malignancies. Accordingly, inhibition of epigenetic regulators is emerging as a promising therapeutic strategy. The acetylation status of lysine residues in histone tails is one of a number of epigenetic post-translational modifications that alter DNA-templated processes, such as transcription, to facilitate malignant transformation. Although histone deacetylases are already being clinically targeted, the role of histone lysine acetyltransferases (KAT) in malignancy is less well characterized. We chose to study this question in the context of acute myeloid leukemia (AML), where, using in vitro and in vivo genetic ablation and knockdown experiments in murine models, we demonstrate a role for the epigenetic regulators CBP and p300 in the induction and maintenance of AML. Furthermore, using selective small molecule inhibitors of their lysine acetyltransferase activity, we validate CBP/p300 as therapeutic targets in vitro across a wide range of human AML subtypes. We proceed to show that growth retardation occurs through the induction of transcriptional changes that induce apoptosis and cell-cycle arrest in leukemia cells and finally demonstrate the efficacy of the KAT inhibitors in decreasing clonogenic growth of primary AML patient samples. Taken together, these data suggest that CBP/p300 are promising therapeutic targets across multiple subtypes in AML.
Asunto(s)
Proteína p300 Asociada a E1A/genética , Epigénesis Genética , Leucemia Mieloide Aguda/genética , Fragmentos de Péptidos/genética , Sialoglicoproteínas/genética , Animales , Apoptosis/efectos de los fármacos , Benzoatos/administración & dosificación , Puntos de Control del Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proteína p300 Asociada a E1A/biosíntesis , Femenino , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Histona Acetiltransferasas/antagonistas & inhibidores , Histona Acetiltransferasas/genética , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Ratones , Nitrobencenos , Fragmentos de Péptidos/biosíntesis , Pirazoles/administración & dosificación , Pirazolonas , Sialoglicoproteínas/biosíntesisRESUMEN
The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/genética , Regulación del Desarrollo de la Expresión Génica/genética , Genes Homeobox , Proteínas con Dominio LIM/genética , Mesodermo/metabolismo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/embriología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Adaptadoras Transductoras de Señales/deficiencia , Animales , Secuencia de Bases , Línea Celular Tumoral , Proliferación Celular , Cromatina/genética , Secuencia Conservada , Elementos E-Box , Extremidades/embriología , Técnicas de Silenciamiento del Gen , Proteínas de Homeodominio/metabolismo , Humanos , Intrones/genética , Proteínas con Dominio LIM/deficiencia , Ratones , Datos de Secuencia Molecular , Fenotipo , Leucemia-Linfoma Linfoblástico de Células T Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Proteínas Proto-Oncogénicas/deficiencia , Activación Transcripcional/genéticaRESUMEN
There were 3 cases of Fitz-Hugh-Curtis syndrome,--pelvic inflammatory disease (PID) complications and perihepatitis,--caused by Chlamydia trachomatis infection. All 3 patients complained of sudden right upper quadrant pain in addition to PID symptoms. Enzyme immunoassay of uterine cervical specimens revealed that the positive chlamydial antigen and serum antibody titer against anti-Chlamydia trachomatis were also high. In all cases the laparoscopy revealed findings of perihepatitis on the anterior surface of the right hepatic lobe. In 2 cases, typical violin-string adhesions were also observed between the liver capsule and parietal peritoneum. In both cases, adhesiolysis was conducted during the laparoscopy.