RESUMEN
Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase that regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD) that plays a vital role in energy metabolism. Here, we show that KPT-9274 strongly inhibits B-ALL cell growth regardless of cytogenetic abnormalities. We also demonstrate the potent in vivo efficacy and tolerability of KPT-9274 in a patient-derived xenograft murine model of B-ALL. Interestingly, although KPT-9274 is a dual PAK4/NAMPT inhibitor, B-ALL cell growth inhibition by KPT-9274 was largely abolished with nicotinic acid supplementation, indicating that the inhibitory effects on B-ALL cells are mainly exerted by NAD+ depletion through NAMPT inhibition. Moreover, we have found that the extreme susceptibility of B-ALL cells to NAMPT inhibition is related to the reduced cellular NAD+ reserve. NAD+ depletion may be a promising alternative approach to treating patients with B-ALL.
Asunto(s)
NAD/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras B/metabolismo , Acrilamidas/química , Acrilamidas/farmacología , Aminopiridinas/química , Aminopiridinas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Citocinas/antagonistas & inhibidores , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , Nicotinamida Fosforribosiltransferasa/antagonistas & inhibidores , Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Transducción de Señal/efectos de los fármacos , Ensayos Antitumor por Modelo de Xenoinjerto , Quinasas p21 Activadas/antagonistas & inhibidoresRESUMEN
Partial tandem duplication of MLL (MLL-PTD) characterizes acute myeloid leukemia (AML) patients often with a poor prognosis. To understand the order of occurrence of MLL-PTD in relation to other major AML mutations and to identify novel mutations that may be present in this unique AML molecular subtype, exome and targeted sequencing was performed on 85 MLL-PTD AML samples using HiSeq-2000. Genes involved in the cohesin complex (STAG2), a splicing factor (U2AF1) and a poorly studied gene, MGA were recurrently mutated, whereas NPM1, one of the most frequently mutated AML gene, was not mutated in MLL-PTD patients. Interestingly, clonality analysis suggests that IDH2/1, DNMT3A, U2AF1 and TET2 mutations are clonal and occur early, and MLL-PTD likely arises after these initial mutations. Conversely, proliferative mutations (FLT3, RAS), typically appear later, are largely subclonal and tend to be unstable. This study provides important insights for understanding the relative importance of different mutations for defining a targeted therapeutic strategy for MLL-PTD AML patients.
Asunto(s)
N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/genética , Mutación , Proteína de la Leucemia Mieloide-Linfoide/genética , Proliferación Celular/genética , Células Clonales , Exoma , Humanos , Tasa de Mutación , Nucleofosmina , Secuencias Repetidas en Tándem , Factores de TiempoAsunto(s)
N-Metiltransferasa de Histona-Lisina/genética , Leucemia Mieloide Aguda/genética , Proteína de la Leucemia Mieloide-Linfoide/genética , Tirosina Quinasa 3 Similar a fms/genética , Adulto , Anciano , Anciano de 80 o más Años , Proteínas Potenciadoras de Unión a CCAAT/genética , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación/genética , Proteínas Nucleares/genética , Nucleofosmina , Pronóstico , Recurrencia , Secuencias Repetidas en Tándem/genética , Proteína p53 Supresora de Tumor/genética , Adulto JovenRESUMEN
ZNF750 controls epithelial homeostasis by regulating epidermal-differentiation genes, a role underscored by its pathogenic mutations in esophageal squamous cell cancers (SCCs). However, the precise role of ZNF750 in SCC cell biology remains unclear. In this study, we report that ZNF750 is exclusively deleted, mutated and underexpressed in human SCCs, and low ZNF750 expression is associated with poor survival. Restoration of wildtype, but not mutant ZNF750 protein uniquely inhibited the malignant phenotypes of SCC cells both in vitro and in vivo. Notably, ZNF750 promoted the expression of a long non-coding RNA (TINCR), which mediated both cancer-inhibition and differentiation-induction effects of ZNF750. In addition, ZNF750 potently suppressed cell migration by directly inhibiting the transactivation of LAMC2. Together, our findings characterize ZNF750 as a crucial SCC-specific suppressor and uncover its novel anticancer-associated functions.
Asunto(s)
Carcinoma de Células Escamosas/genética , Neoplasias Esofágicas/genética , Genes Supresores de Tumor , Factores de Transcripción/genética , Animales , Carcinoma de Células Escamosas/fisiopatología , Diferenciación Celular/genética , Línea Celular Tumoral , Linaje de la Célula , Movimiento Celular , ADN de Neoplasias , Neoplasias Esofágicas/fisiopatología , Femenino , Eliminación de Gen , Regulación Neoplásica de la Expresión Génica , Células HEK293 , Neoplasias de Cabeza y Cuello/genética , Humanos , Laminina/genética , Ratones , Ratones Endogámicos NOD , Mutación , Análisis de Secuencia por Matrices de Oligonucleótidos , Pronóstico , ARN Largo no Codificante , Factores de Transcripción/metabolismo , Transcriptoma , Proteínas Supresoras de Tumor/metabolismo , Neoplasias del Cuello Uterino/genética , Neoplasias del Cuello Uterino/fisiopatologíaRESUMEN
Acute promyelocytic leukemia (APL) is a subtype of myeloid leukemia characterized by differentiation block at the promyelocyte stage. Besides the presence of chromosomal rearrangement t(15;17), leading to the formation of PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha) fusion, other genetic alterations have also been implicated in APL. Here, we performed comprehensive mutational analysis of primary and relapse APL to identify somatic alterations, which cooperate with PML-RARA in the pathogenesis of APL. We explored the mutational landscape using whole-exome (n=12) and subsequent targeted sequencing of 398 genes in 153 primary and 69 relapse APL. Both primary and relapse APL harbored an average of eight non-silent somatic mutations per exome. We observed recurrent alterations of FLT3, WT1, NRAS and KRAS in the newly diagnosed APL, whereas mutations in other genes commonly mutated in myeloid leukemia were rarely detected. The molecular signature of APL relapse was characterized by emergence of frequent mutations in PML and RARA genes. Our sequencing data also demonstrates incidence of loss-of-function mutations in previously unidentified genes, ARID1B and ARID1A, both of which encode for key components of the SWI/SNF complex. We show that knockdown of ARID1B in APL cell line, NB4, results in large-scale activation of gene expression and reduced in vitro differentiation potential.
