RESUMEN
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. To identify novel candidates for targeted therapy, we performed a comprehensive transcriptome analysis identifying MondoA (MLXIP) - a transcription factor regulating glycolysis - to be overexpressed in ALL compared to normal tissues. Using microarray-profiling, gene-set enrichment analysis, RNA interference and functional assays we show that MondoA overexpression increases glucose catabolism and maintains a more immature phenotype, which is associated with enhanced survival and clonogenicity of leukemia cells. These data point to an important contribution of MondoA to leukemia aggressiveness and make MondoA a potential candidate for targeted treatment of ALL.
Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/fisiología , Diferenciación Celular/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Apoptosis/efectos de los fármacos , Apoptosis/genética , Apoptosis/fisiología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Diferenciación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/genética , Evaluación Preclínica de Medicamentos , Perfilación de la Expresión Génica , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Células Hep G2 , Humanos , Células Jurkat , Análisis por Micromatrices , Invasividad Neoplásica , Leucemia-Linfoma Linfoblástico de Células Precursoras/fisiopatología , ARN Interferente Pequeño/farmacología , Células Tumorales Cultivadas , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
Severe acute graft versus host disease (GvHD) is a life-threatening complication after allogeneic hematopoietic stem cell transplantation. Human mesenchymal stromal cells (MSCs) play an important role in endogenous tissue repair and possess strong immune-modulatory properties making them a promising tool for the treatment of steroid-refractory GvHD. To date, a few reports exist on the use of MSCs in treatment of GvHD in children indicating that children tend to respond better than adults, albeit with heterogeneous results.We here present a review of the literature and the clinical course of two instructive pediatric patients with acute steroid-refractory GvHD after haploidentical stem cell transplantation, which exemplify the beneficial effects of third-party transplanted MSCs in treatment of acute steroid-refractory GvHD. Moreover, we provide a meta-analysis of clinical studies addressing the outcome of patients with steroid-refractory GvHD and treatment with MSCs in adults and in children (n = 183; 122 adults, 61 children). Our meta-analysis demonstrates that the overall response-rate is high (73.8%) and confirms, for the first time, that children indeed respond better to treatment of GvHD with MSCs than adults (complete response 57.4% vs. 45.1%, respectively).These data emphasize the significance of this therapeutic approach especially in children and indicate that future prospective studies are needed to assess the reasons for the observed differential response-rates in pediatric and adult patients.
