RESUMEN
Wilms' tumor is the most common type of childhood kidney cancer. To improve risk stratification and identify novel therapeutic targets for patients with Wilms' tumor, we used high-resolution mass spectrometry proteomics to identify urine tumor markers associated with Wilms' tumor relapse. We determined the urine proteomes at diagnosis of 49 patients with Wilms' tumor, non-Wilms' tumor renal tumors, and age-matched controls, leading to the quantitation of 6520 urine proteins. Supervised analysis revealed specific urine markers of renal rhabdoid tumors, kidney clear cell sarcomas, renal cell carcinomas as well as those detected in patients with cured and relapsed Wilms' tumor. In particular, urine prohibitin was significantly elevated at diagnosis in patients with relapsed as compared with cured Wilms' tumor. In a validation cohort of 139 patients, a specific urine prohibitin ELISA demonstrated that prohibitin concentrations greater than 998 ng/mL at diagnosis were significantly associated with ultimate Wilms' tumor relapse. Immunohistochemical analysis revealed that prohibitin was highly expressed in primary Wilms' tumor specimens and associated with disease stage. Using functional genetic experiments, we found that prohibitin was required for the growth and survival of Wilms' tumor cells. Overexpression of prohibitin was sufficient to block intrinsic mitochondrial apoptosis and to cause resistance to diverse chemotherapy drugs, at least in part by dysregulating factors that control apoptotic cytochrome c release from mitochondrial cristae. Thus, urine prohibitin may improve therapy stratification, noninvasive monitoring of treatment response, and early disease detection. In addition, therapeutic targeting of chemotherapy resistance induced by prohibitin dysregulation may offer improved therapies for patients with Wilms' and other relapsed or refractory tumors.
Asunto(s)
Biomarcadores de Tumor/orina , Neoplasias Renales/diagnóstico , Recurrencia Local de Neoplasia/diagnóstico , Proteínas Represoras/orina , Tumor de Wilms/diagnóstico , Adolescente , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Apoptosis/efectos de los fármacos , Biomarcadores de Tumor/antagonistas & inhibidores , Estudios de Casos y Controles , Línea Celular Tumoral , Niño , Preescolar , Estudios de Cohortes , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Células HEK293 , Humanos , Lactante , Riñón/patología , Riñón/cirugía , Neoplasias Renales/patología , Neoplasias Renales/terapia , Neoplasias Renales/orina , Masculino , Microscopía Electrónica de Transmisión , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Mitocondrias/ultraestructura , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/orina , Nefrectomía , Prohibitinas , Proteómica , Interferencia de ARN , Proteínas Represoras/antagonistas & inhibidores , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Análisis de Matrices Tisulares , Tumor de Wilms/patología , Tumor de Wilms/terapia , Tumor de Wilms/orinaRESUMEN
In acute myeloid leukemia (AML), chemotherapy resistance remains prevalent and poorly understood. Using functional proteomics of patient AML specimens, we identified MEF2C S222 phosphorylation as a specific marker of primary chemoresistance. We found that Mef2cS222A/S222A knock-in mutant mice engineered to block MEF2C phosphorylation exhibited normal hematopoiesis, but were resistant to leukemogenesis induced by MLL-AF9 MEF2C phosphorylation was required for leukemia stem cell maintenance and induced by MARK kinases in cells. Treatment with the selective MARK/SIK inhibitor MRT199665 caused apoptosis and conferred chemosensitivity in MEF2C-activated human AML cell lines and primary patient specimens, but not those lacking MEF2C phosphorylation. These findings identify kinase-dependent dysregulation of transcription factor control as a determinant of therapy response in AML, with immediate potential for improved diagnosis and therapy for this disease.Significance: Functional proteomics identifies phosphorylation of MEF2C in the majority of primary chemotherapy-resistant AML. Kinase-dependent dysregulation of this transcription factor confers susceptibility to MARK/SIK kinase inhibition in preclinical models, substantiating its clinical investigation for improved diagnosis and therapy of AML. Cancer Discov; 8(4); 478-97. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 371.
