RESUMEN
Diamond-Blackfan anemia (DBA) results from haploinsufficiency of ribosomal protein subunits in hematopoietic progenitors in the earliest stages of committed erythropoiesis. Nemo-like kinase (NLK) is chronically hyperactivated in committed erythroid progenitors and precursors in multiple human and murine models of DBA. Inhibition of NLK activity and suppression of NLK expression both improve erythroid expansion in these models. Metformin is a well-tolerated drug for type 2 diabetes with multiple cellular targets. Here we demonstrate that metformin improves erythropoiesis in human and zebrafish models of DBA. Our data indicate that the effects of metformin on erythroid proliferation and differentiation are mediated by suppression of NLK expression through induction of miR-26a, which recognizes a binding site within the NLK 3' untranslated region (3'UTR) to facilitate transcript degradation. We propose that induction of miR-26a is a potentially novel approach to treatment of DBA and could improve anemia in DBA patients without the potentially adverse side effects of metformin in a DBA patient population.
Asunto(s)
Anemia de Diamond-Blackfan/tratamiento farmacológico , Eritropoyesis/efectos de los fármacos , Hematínicos/uso terapéutico , Metformina/uso terapéutico , MicroARNs/biosíntesis , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Regiones no Traducidas 3'/genética , Anemia de Diamond-Blackfan/genética , Animales , Células Cultivadas , Ensayo de Unidades Formadoras de Colonias , Modelos Animales de Enfermedad , Eritropoyesis/genética , Regulación de la Expresión Génica/efectos de los fármacos , Genes Reporteros , Hematínicos/farmacología , Humanos , Metformina/farmacología , MicroARNs/genética , Estabilidad del ARN , ARN Interferente Pequeño/farmacología , Proteínas Recombinantes/metabolismo , Especificidad de la Especie , Regulación hacia Arriba/efectos de los fármacos , Pez CebraRESUMEN
PURPOSE OF REVIEW: Rho kinases (ROCKs) are involved in regulating a variety of physiologic functions including cytoskeletal reorganization, migration, adhesion, survival and proliferation. They do so via activating several different downstream substrates such as myosin light chain phosphatase, LIM kinase and ezrin/radixin/moesin proteins. To date, most of the conclusions with regard to the function of ROCKs have involved the use of cell line models, pharmacologic inhibitors and dominant negative approaches. Importantly, the role of ROCK in hematopoiesis or leukemogenesis in the context of whole organism remains poorly understood. RECENT FINDINGS: Recent studies utilizing mice deficient in the expression of ROCK1 have begun to shed some light into the physiologic role(s) of ROCK in both normal and abnormal hematopoiesis. Findings, thus far, suggest that ROCK plays an essential role in regulating growth and survival in different hematopoietic lineages via distinct mechanisms, in part, by utilizing distinct downstream substrates including maintaining the activation of tumor-suppressor genes. SUMMARY: In blood cells, emerging data suggest that ROCK plays an essential role in negatively regulating inflammatory and erythropoietic stress and positively regulates the growth and survival of leukemic cells.
