RESUMEN
Childhood neuroblastoma has a remarkable variability in outcome. Age at diagnosis is one of the most important prognostic factors, with children less than 1 year old having favorable outcomes. Here we study single-cell and single-nuclei transcriptomes of neuroblastoma with different clinical risk groups and stages, including healthy adrenal gland. We compare tumor cell populations with embryonic mouse sympatho-adrenal derivatives, and post-natal human adrenal gland. We provide evidence that low and high-risk neuroblastoma have different cell identities, representing two disease entities. Low-risk neuroblastoma presents a transcriptome that resembles sympatho- and chromaffin cells, whereas malignant cells enriched in high-risk neuroblastoma resembles a subtype of TRKB+ cholinergic progenitor population identified in human post-natal gland. Analyses of these populations reveal different gene expression programs for worst and better survival in correlation with age at diagnosis. Our findings reveal two cellular identities and a composition of human neuroblastoma tumors reflecting clinical heterogeneity and outcome.
Asunto(s)
Neoplasias de las Glándulas Suprarrenales/genética , Glándulas Suprarrenales/metabolismo , Glicoproteínas de Membrana/genética , Proteínas de Neoplasias/genética , Neuroblastoma/genética , Receptor trkB/genética , Transcriptoma , Neoplasias de las Glándulas Suprarrenales/metabolismo , Neoplasias de las Glándulas Suprarrenales/mortalidad , Neoplasias de las Glándulas Suprarrenales/patología , Glándulas Suprarrenales/patología , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Diferenciación Celular , Núcleo Celular/genética , Núcleo Celular/metabolismo , Preescolar , Células Cromafines/metabolismo , Células Cromafines/patología , Diagnóstico Precoz , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Lactante , Masculino , Glicoproteínas de Membrana/metabolismo , Ratones , Proteínas de Neoplasias/clasificación , Proteínas de Neoplasias/metabolismo , Neuroblastoma/metabolismo , Neuroblastoma/mortalidad , Neuroblastoma/patología , Receptor trkB/metabolismo , Medición de Riesgo , Análisis de la Célula Individual , Especificidad de la Especie , Análisis de SupervivenciaRESUMEN
Dephosphorylation of SpoIIAA-P by SpoIIE is strictly dependent on the presence of the bivalent metal ions Mn2+ or Mg2+. Replacement by Ala of one of the four Asp residues, invariant in all representatives of protein phosphatase 2C, completely abolished the SpoIIE phosphatase activity in vitro, whilst replacement of the Asp residues by another acidic amino acid, Glu, had varying effects on the activities of the resulting mutated proteins. D610E and D795E exhibited some residual activity while D628E and D745E were without enzymatic activity. The results suggest that the functional model in which metal-associated water molecules are involved in the dephosphorylation reaction catalyzed by human protein phosphatase 2C alpha can also be applied to the bacterial protein phosphatase 2C-like protein.