RESUMEN
Poly(ADP-ribose)polymerase (PARP)14--a member of the B aggressive lymphoma (BAL) family of macrodomain-containing PARPs--is an ADP ribosyltransferase that interacts with Stat6, enhances induction of certain genes by IL-4, and is expressed in B lymphocytes. We now show that IL-4 enhancement of glycolysis in B cells requires PARP14 and that this process is central to a role of PARP14 in IL-4-induced survival. Thus, enhancements of AMP-activated protein kinase activity restored both IL-4-induced glycolytic activity in Parp14(-/-) B cells and prosurvival signaling by this cytokine. Suppression of apoptosis is central to B-lymphoid oncogenesis, and elevated macro-PARP expression has been correlated with lymphoma aggressiveness. Strikingly, PARP14 deficiency delayed B lymphomagenesis and reversed the block to B-cell maturation driven by the Myc oncogene. Collectively, these findings reveal links between a mammalian ADP ribosyltransferase, cytokine-regulated metabolic activity, and apoptosis; show that PARP14 influences Myc-induced oncogenesis; and suggest that the PARP14-dependent capacity to increase cellular metabolic rates may be an important determinant of lymphoma pathobiology.
Asunto(s)
Linfocitos B/metabolismo , Glucólisis , Linfoma/metabolismo , Poli(ADP-Ribosa) Polimerasas/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Animales , Apoptosis/efectos de los fármacos , Linfocitos B/patología , Transporte Biológico/efectos de los fármacos , Células Cultivadas , Activación Enzimática/efectos de los fármacos , Femenino , Glucosa/metabolismo , Glucosa/farmacocinética , Immunoblotting , Etiquetado Corte-Fin in Situ , Interleucina-4/farmacología , Linfoma/genética , Linfoma/patología , Masculino , Ratones , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Fosforilación Oxidativa/efectos de los fármacos , Poli(ADP-Ribosa) Polimerasas/genética , Factor de Transcripción STAT6/genética , Factor de Transcripción STAT6/metabolismo , Análisis de SupervivenciaRESUMEN
IMPORTANCE: Moyamoya syndrome is a rare, occlusive cerebrovascular arteriopathy with significant risk for stroke. Populations that frequently undergo otolaryngologic procedures, including patients with Down syndrome and sickle cell disease, are particularly at risk for moyamoya. The initial presentation of moyamoya syndrome as stroke in the perioperative period of an otolaryngologic procedure has not been reported. OBSERVATIONS: A retrospective medical record review assessed the relationship of otolaryngologic operations and the onset of moyamoya symptoms. Moyamoya syndrome was present in 137 patients. Of these, 19 patients underwent otolaryngologic procedures; 3 children had strokes 2 to 4 days after adenotonsillectomy, including 2 children with Down syndrome. Intraoperative carotid artery injury was considered but was proven not to be the cause of stroke. Bilateral moyamoya disease was diagnosed in all 3 patients via vascular imaging studies; all subsequently underwent revascularization procedures. CONCLUSIONS AND RELEVANCE: Clinicians should be aware of an elevated prevalence of moyamoya syndrome in Down syndrome and sickle cell disease populations and should consider moyamoya syndrome in the differential diagnosis of postoperative stroke. Stroke risk is magnified in the perioperative setting related to perioperative dehydration and hypotension. Awareness and screening for cerebral vasculopathy in high-risk populations could prompt measures to decrease the occurrence of postoperative strokes after adenotonsillectomies.