RESUMEN
Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with -7/del7q and 11 with normal karyotype) with 23 CD34+ preparations from healthy bone marrow donors. SKI, a nuclear oncogene, was highly up regulated. In a second set of 183 AML patients analyzed with real-time PCR, the highest expression level of SKI in AML with -7/del7q could be confirmed. As previously described, Ski associates with the retinoic acid receptor (RAR) complex and can repress transcription. We wanted to investigate the interference of Ski with RARalpha signaling in AML. Ski was co-immunoprecipitated and colocalized with RARalpha. We also found that overexpression of wild-type Ski inhibited the prodifferentiating effects of retinoic acid in U937 leukemia cells. Mutant Ski, lacking the N-CoR binding, was no more capable of repressing RARalpha signaling. The inhibition by wild-type Ski could partially be reverted by the histone deacetylase blocking agent valproic acid. In conclusion, Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARalpha signaling.
Asunto(s)
Proteínas de Unión al ADN/metabolismo , Leucemia Mieloide/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , Receptores de Ácido Retinoico/metabolismo , Transducción de Señal , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Deleción Cromosómica , Cromosomas Humanos Par 7 , Inhibidores Enzimáticos/farmacología , Femenino , Técnica del Anticuerpo Fluorescente , Inhibidores de Histona Desacetilasas , Humanos , Leucemia Mieloide/genética , Masculino , Persona de Mediana Edad , Receptores de Ácido Retinoico/antagonistas & inhibidores , Ácido Valproico/farmacologíaRESUMEN
The retroviral oncogene v-myb encodes a transcription factor (v-Myb) which disrupts the myelomonocytic differentiation program and transforms myelomonocytic cells in vivo and in vitro. It is thought that v-Myb exerts its biological effects by deregulating the expression of specific target genes, most of which are still unknown. c-myb, the cellular progenitor of v-myb, is expressed in all immature hematopoietic cells and is presumed to regulate the expression of genes that are essential for the development of the hematopoietic system. Recently, we have identified the chicken Pdcd4 gene as a novel v-myb target gene. Pdcd4 has originally been identified in a screen for genes upregulated in apoptotic cells and, more recently, has been implicated in tumor progression. As a myb-regulated gene Pdcd4 is of interest because unlike most other myb target genes it is expressed in a broad spectrum of hematopoietic cells. As a first step to study the regulation of Pdcd4 expression in more detail, we here report the identification and preliminary characterization of the myb-inducible promoter of the Pdcd4 gene.