Mecanismos genéticos de activación de la vía de transducción de señal JAK2/STAT5 en neoplasias hematológicasidentificación y caracterización de nuevos genes diana

Resumo

Genetic mechanisms of JAK2/STAT5 signalling pathway activation in haematological neoplasms: identification and characterization of new target genes. Chronic myeloproliferative neoplasms (CMPNs) are clonal disorders characterized by the abnormal proliferation of myeloid hematopoietic cells. The JAK2/STAT5 signalling pathway promotes essential hematopoietic events and is frequently deregulated in patients with these diseases. One of the most recurrent alterations in CMPNs is the activating mutation V617F in JAK2, which leads to the development of three diseases with distinct phenotypic features: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). None of the explanations proposed so far has been able to clarify these phenotypic differences. This suggests that there might be other components of the JAK2/STAT5 pathway playing a significant role in the progress of these CMPNs. Therefore, it is necessary to identify new JAK2/STAT5 target genes and new regulatory loops that could be involved in the development of these neoplasms. In this study, we have identified 14 genes and 32 microRNAs regulated by the JAK2/STAT5 pathway and we have created two networks that show the predicted interactions between them. Seven of these genes have been confirmed as direct STAT5 target genes. One of them, LIF, has been found to be upregulated in haematological cell lines with activated JAK2/STAT5 pathway as well as in patients with CMPNs, particularly those with PMF or mutations in JAK2 or MPL genes. We have also proved the direct interaction between LIF and two microRNAs, hsa-miR-296-5p and hsa-miR-650. Hence, we proposed that our networks can be used as tools to identify new JAK2/STAT5 regulatory loops potentially altered in these haematological malignancies.