RESUMEN
With intensified pediatric-like therapy and genetic disease dissection, the field of adult acute lymphoblastic leukemia (ALL) has evolved recently. In this new context, we aimed to reassess the value of conventional risk factors with regard to new genetic alterations and early response to therapy, as assessed by immunoglobulin/T-cell receptor minimal residual disease (MRD) levels. The study was performed in 423 younger adults with Philadelphia chromosome-negative ALL in first remission (265 B-cell precursor [BCP] and 158 T-cell ALL), with cumulative incidence of relapse (CIR) as the primary end point. In addition to conventional risk factors, the most frequent currently available genetic alterations were included in the analysis. A higher specific hazard of relapse was independently associated with postinduction MRD level ≥10(-4) and unfavorable genetic characteristics (ie, MLL gene rearrangement or focal IKZF1 gene deletion in BCP-ALL and no NOTCH1/FBXW7 mutation and/or N/K-RAS mutation and/or PTEN gene alteration in T-cell ALL). These 2 factors allowed definition of a new risk classification that is strongly associated with higher CIR and shorter relapse-free and overall survival. These results indicate that genetic abnormalities are important predictors of outcome in adult ALL not fully recapitulated by early response to therapy. Patients included in this study were treated in the multicenter GRAALL-2003 and GRAALL-2005 trials. Both trials were registered at http://www.clinicaltrials.gov as #NCT00222027 and #NCT00327678, respectively.
Asunto(s)
Biomarcadores de Tumor/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Adolescente , Adulto , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Neoplasia Residual , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidad , Leucemia-Linfoma Linfoblástico de Células Precursoras/patología , Pronóstico , Recurrencia , Estudios Retrospectivos , Análisis de Supervivencia , Adulto JovenRESUMEN
Acute kidney injury (AKI) is considered largely reversible based on the capacity of surviving tubular cells to dedifferentiate and replace lost cells via cell division. Here we show by tracking individual tubular cells in conditional Pax8/Confetti mice that kidney function is recovered after AKI despite substantial tubular cell loss. Cell cycle and ploidy analysis upon AKI in conditional Pax8/FUCCI2aR mice and human biopsies identify endocycle-mediated hypertrophy of tubular cells. By contrast, a small subset of Pax2+ tubular progenitors enriches via higher stress resistance and clonal expansion and regenerates necrotic tubule segments, a process that can be enhanced by suitable drugs. Thus, renal functional recovery upon AKI involves remnant tubular cell hypertrophy via endocycle and limited progenitor-driven regeneration that can be pharmacologically enhanced.
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Lesión Renal Aguda/patología , Lesión Renal Aguda/fisiopatología , Lesión Renal Aguda/genética , Células Madre Adultas/patología , Animales , Ciclo Celular , Desdiferenciación Celular , Aumento de la Célula , Linaje de la Célula , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Femenino , Inhibidores de Histona Desacetilasas/farmacología , Humanos , Túbulos Renales/efectos de los fármacos , Túbulos Renales/patología , Túbulos Renales/fisiopatología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor de Transcripción PAX2/metabolismo , Factor de Transcripción PAX8/metabolismo , Ploidias , Regeneración/efectos de los fármacos , Análisis de la Célula IndividualRESUMEN
Alveolar rhabdomyosarcoma is a life-threatening myogenic cancer of children and adolescent young adults, driven primarily by the chimeric transcription factor PAX3-FOXO1. The mechanisms by which PAX3-FOXO1 dysregulates chromatin are unknown. We find PAX3-FOXO1 reprograms the cis-regulatory landscape by inducing de novo super enhancers. PAX3-FOXO1 uses super enhancers to set up autoregulatory loops in collaboration with the master transcription factors MYOG, MYOD, and MYCN. This myogenic super enhancer circuitry is consistent across cell lines and primary tumors. Cells harboring the fusion gene are selectively sensitive to small-molecule inhibition of protein targets induced by, or bound to, PAX3-FOXO1-occupied super enhancers. Furthermore, PAX3-FOXO1 recruits and requires the BET bromodomain protein BRD4 to function at super enhancers, resulting in a complete dependence on BRD4 and a significant susceptibility to BRD inhibition. These results yield insights into the epigenetic functions of PAX3-FOXO1 and reveal a specific vulnerability that can be exploited for precision therapy.Significance: PAX3-FOXO1 drives pediatric fusion-positive rhabdomyosarcoma, and its chromatin-level functions are critical to understanding its oncogenic activity. We find that PAX3-FOXO1 establishes a myoblastic super enhancer landscape and creates a profound subtype-unique dependence on BET bromodomains, the inhibition of which ablates PAX3-FOXO1 function, providing a mechanistic rationale for exploring BET inhibitors for patients bearing PAX-fusion rhabdomyosarcoma. Cancer Discov; 7(8); 884-99. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 783.
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Elementos de Facilitación Genéticos/genética , Proteínas Nucleares/genética , Proteínas de Fusión Oncogénica/genética , Factores de Transcripción Paired Box/genética , Rabdomiosarcoma Alveolar/tratamiento farmacológico , Factores de Transcripción/genética , Animales , Proteínas de Ciclo Celular , Línea Celular Tumoral , Cromatina/genética , Elementos de Facilitación Genéticos/efectos de los fármacos , Epigénesis Genética/efectos de los fármacos , Epigénesis Genética/genética , Femenino , Humanos , Masculino , Ratones , Proteína MioD/genética , Miogenina/genética , Proteína Proto-Oncogénica N-Myc/genética , Unión Proteica/genética , Dominios Proteicos/genética , Rabdomiosarcoma Alveolar/genética , Rabdomiosarcoma Alveolar/patología , Bibliotecas de Moléculas Pequeñas/administración & dosificación , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Podocyte loss is a general mechanism of glomerular dysfunction that initiates and drives the progression of chronic kidney disease, which affects 10% of the world population. Here, we evaluate whether the regenerative response to podocyte injury influences chronic kidney disease outcome. In models of focal segmental glomerulosclerosis performed in inducible transgenic mice where podocytes are tagged, remission or progression of disease was determined by the amount of regenerated podocytes. When the same model was established in inducible transgenic mice where renal progenitors are tagged, the disease remitted if renal progenitors successfully differentiated into podocytes, while it persisted if differentiation was ineffective, resulting in glomerulosclerosis. Treatment with BIO, a GSK3s inhibitor, significantly increased disease remission by enhancing renal progenitor sensitivity to the differentiation effect of endogenous retinoic acid. These results establish renal progenitors as critical determinants of glomerular disease outcome and a pharmacological enhancement of their differentiation as a possible therapeutic strategy.
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Diferenciación Celular , Podocitos/citología , Regeneración , Insuficiencia Renal Crónica/patología , Células Madre/citología , Animales , Células Cultivadas , Glucógeno Sintasa Quinasa 3/antagonistas & inhibidores , Indoles/farmacología , Indoles/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Oximas/farmacología , Oximas/uso terapéutico , Podocitos/efectos de los fármacos , Podocitos/metabolismo , Insuficiencia Renal Crónica/tratamiento farmacológico , Células Madre/efectos de los fármacos , Células Madre/metabolismoRESUMEN
BACKGROUND: The CF transmembrane conductance regulator (CFTR), whose mutations cause cystic fibrosis (CF), depends on ATP for activation and transport function. Availability of ATP in the cell and even more in specific cellular microcompartments often depends on a functional creatine kinase system, which provides the 'energy buffer' phosphocreatine. Creatine supplementation has been shown to increase phosphocreatine levels, thus promoting muscle growth and strength in athletes and having protective effects in neuromuscular disorders. AIM: To test clinically, if creatine supplementation improves maximal isometric muscle strength (MIMS), lung function and CFTR channel activity in patients with CF, and to determine enzymatic activity of creatine kinase in respiratory epithelial cells. METHODS: In an open-label pilot study 18 CF patients (8-18-year-old) with pancreatic insufficiency and mild to moderate lung disease received daily creatine supplementation during 12 weeks. Patients were monitored during 24-36 weeks. Enzymatic activity of creatine kinase was measured in primary epithelial cell cultures. RESULTS: After creatine supplementation, there was no change in lung function and sweat electrolyte concentrations, possibly due to the very low creatine kinase activities detected in respiratory epithelia. However, the patients consistently showed significantly increased MIMS (18.4%; P < 0.0001), as well as improved general well-being, as assessed by a standardized questionnaire. Except for one patient with transient muscle pain, no side effects were reported. CONCLUSIONS: Our pilot study suggests, that creatine supplementation should be further evaluated as a possible clinically beneficial adjuvant therapy for patients with CF to increase muscle strength, body-weight and well-being.