MicroRNA-125b (miR-125b) is highly expressed in many cancers such as B cell lymphomas and myeloid leukemia and inflammatory disorders such as rheumatoid arthritis, atopic dermatitis, and multiple sclerosis. However, the underlying mechanism of miR-125b dysregulation remains to be explored. Relevant to myeloid leukemia, C/EBPα is frequently mutated in AML, but surprisingly, none of the observed mutations result in full ablation of the gene, indicating that its activity is required for AML. Interestingly, C/EBPα in normal hematopoiesis and in AML is able to induce the expression of some miRNAs during myeloid development and leukemia. Previously, it has been shown that the manifestation of Hailey- Hailey disease was in part dependent on Notch1 downmodulation mediated by miR-125b upregulation. Notably, while the involvement of Notch signaling as an oncogene in acute lymphoblastic leukemia (T-ALL) is well characterized, Notch signaling has been described as a tumor suppressor in myeloid malignancies, like acute myeloid leukemia (AML), where the activation of Notch1 is silenced. In this study we found that C/EBPα positively regulated miR-125b expression and contributes to the up-regulation of this microRNA in AML. We observed the binding of C/EBPα to the miR-125b promoter in cells where Notch1 is not activated, and that C/EBPα negative cells display decreased expression of miR-125b and higher activation of Notch signaling pathway. Furthermore, by transient and lentivirus transfection, we observed that miR-125b targets Notch1. We have thus identified C/EBPα as a novel key regulator of the positive control of miR-125b expression in acute myeloid leukemia. To what extent C/EBPα contributes to myeloid transformation, is unclear. Our study demonstrates the existence of C/EBPα/miR-125b oncogenic axis, further providing evidence that C/EBPα is required for AML, and we suggest that miR-125b dysregulation plays a critical role in the differential expression and activity of Notch1 between T-ALL and AML.
The deregulated expression of miR-125b in acute myeloid leukemia is dependent on the transcription factor C/EBPα / VARGAS ROMERO, PAULA ESTEFANIA. - (2015 Aug 16).
|Titolo:||The deregulated expression of miR-125b in acute myeloid leukemia is dependent on the transcription factor C/EBPα.|
|Data di discussione:||16-ago-2015|
|Appartiene alla tipologia:||07a Tesi di Dottorato|