Asunto(s)
Calreticulina/genética , Micropartículas Derivadas de Células/patología , Janus Quinasa 2/genética , Mutación , Trombocitemia Esencial/patología , Anciano , Micropartículas Derivadas de Células/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Trombocitemia Esencial/complicaciones , Trombocitemia Esencial/genética , Trombosis/etiologíaRESUMEN
The transcription factor, CCAAT enhancer binding protein alpha (C/EBPα), is crucial for granulopoiesis and is deregulated by various mechanisms in acute myeloid leukemia (AML). Mutations in the CEBPA gene are reported in 10% of human patients with AML. Even though the C/EBPα mutants are known to display distinct biologic function during leukemogenesis, the molecular basis for this subtype of AML remains elusive. We have recently showed the significance of deregulation of C/EBPα-regulated microRNA (miR) in AML. In this study, we report that miR-34a is a novel target of C/EBPα in granulopoiesis. During granulopoiesis, miR-34a targets E2F3 and blocks myeloid cell proliferation. Analysis of AML samples with CEBPA mutations revealed a lower expression of miR-34a and elevated levels of E2F3 as well as E2F1, a transcriptional target of E2F3. Manipulation of miR-34a reprograms granulocytic differentiation of AML blast cells with CEBPA mutations. These results define miR-34a as a novel therapeutic target in AML with CEBPA mutations.
