RESUMEN
Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple café-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status in 230 paediatric lymphoblastic and acute myeloblastic leukaemias (AMLs). We found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome. In this patient, the leukaemia blasts karyotype showed a SPRED1 loss of heterozygosity, confirming SPRED1 as a tumour suppressor. Our observation confirmed that acute leukaemias are rare complications of the Legius syndrome. Moreover, SPRED1 was significantly decreased at RNA and protein levels in the majority of AMLs at diagnosis compared with normal or paired complete remission bone marrows. SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs.
Asunto(s)
Manchas Café con Leche/genética , Genes ras/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Leucemia Mieloide Aguda/genética , Proteínas de la Membrana/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Proteínas Adaptadoras Transductoras de Señales , Adolescente , Manchas Café con Leche/complicaciones , Manchas Café con Leche/patología , Niño , Preescolar , Femenino , Regulación Neoplásica de la Expresión Génica , Genes Supresores de Tumor , Humanos , Lactante , Recién Nacido , Péptidos y Proteínas de Señalización Intracelular/biosíntesis , Leucemia Mieloide Aguda/complicaciones , Leucemia Mieloide Aguda/patología , Pérdida de Heterocigocidad/genética , Masculino , Proteínas de la Membrana/biosíntesis , Mutación , Neurofibromina 1/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/complicaciones , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patologíaRESUMEN
The early-response gene product IEX-1 (also known as IER3) was recently found to interact with the anti-apoptotic Bcl-2 family member, myeloid cell leukemia-1 (Mcl-1). In this study we show that this interaction specifically and timely controls the accumulation of Mcl-1 in the nucleus in response to DNA damage. The IEX-1 protein is rapidly induced by γ-irradiation, genotoxic agents or replication inhibitors, in a way dependent on ataxia telangiectasia mutated (ATM) activity and is necessary for Mcl-1 nuclear translocation. Conversely, IEX-1 protein proteasomal degradation triggers the return of Mcl-1 to the cytosol. IEX-1 and Mcl-1 are integral components of the DNA damage response. Loss of IEX-1 or Mcl-1 leads to genomic instability and increased sensitivity to genotoxic and replicative stresses. The two proteins cooperate to maintain Chk1 activation and G2 checkpoint arrest. Mcl-1 nuclear translocation may foster checkpoint and improve the tumor resistance to DNA damage-based cancer therapies. Deciphering the pathways involved in IEX-1 degradation should lead to the discovery of new therapeutic targets to increase sensitivity of tumor cells to chemotherapy.