Abstract
microRNAs (miRNAs) are relevant in the pathogenesis of primary myelofibrosis (PMF) but our understanding is limited to specific target genes and the overall systemic scenario islacking. By both knowledge-based and ab initio approaches for comparative analysis of CD34+ cells of PMF patients and healthy controls, we identified the deregulated pathways involving miRNAs and genes and new transcriptional and post-transcriptional regulatory circuits in PMF cells. These converge in a unique and integrated cellular process, in which the role of specific miRNAs is to wire, co-regulate and allow a fine crosstalk between the involved processes. The PMF pathway includes Akt signaling, linked to Rho GTPases, CDC42, PLD2, PTEN crosstalk with the hypoxia response and Calcium-linked cellular processes connected to cyclic AMP signaling. Nested on the depicted transcriptional scenario, predicted circuits are reported, opening new hypotheses. Links between miRNAs (miR-106a-5p, miR-20b-5p, miR-20a-5p, miR-17-5p, miR-19b-3p and let-7d-5p) and key transcription factors (MYCN, ATF, CEBPA, REL, IRF and FOXJ2) and their common target genes tantalizingly suggest new path to approach the disease. The study provides a global overview of transcriptional and post-transcriptional deregulations in PMF, and, unifying consolidated and predicted data, could be helpful to identify new combinatorial therapeutic strategy. Interactive PMF network model: http://compgen.bio.unipd.it/pmf-net/.
Highlights
MicroRNAs are relevant in the pathogenesis of primary myelofibrosis (PMF) but our understanding is limited to specific target genes and the overall systemic scenario islacking
The PMF pathway includes Akt signaling, linked to Rho GTPases, CDC42, PLD2, PTEN crosstalk with the hypoxia response and Calcium-linked cellular processes connected to cyclic AMP signaling
Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) that, with essential thrombocythemia and polycythemia vera, constitutes a heterogeneous group of Philadelphia-negative clonal hematopoietic stem cell (HSC) disorders associated with overproduction of mature myeloid cells
Summary
Primary myelofibrosis (PMF) is a chronic myeloproliferative neoplasm (MPN) that, with essential thrombocythemia and polycythemia vera, constitutes a heterogeneous group of Philadelphia-negative clonal hematopoietic stem cell (HSC) disorders associated with overproduction of mature myeloid cells. Important progresses in molecular characterization of MPNs pathogenesis have been done in the last years. Several evidences indicate that these mutations are not sufficient for disease initiation and progression and that the phenotypes of the disease are highly heterogeneous, suggesting that other unknown genetic or epigenetic factors might be involved[3,4,5,6,7,8,9,10,11,12,13,14,15] and that the mutation order could matter:[16] driver mutations can precede or follow additional somatic mutations in other myeloid genes. Recently, it has been demonstrated that most of these genes are associated with age-related clonal hematopoiesis in normal elderly subjects, suggesting that pre-malignant clones may be present many years before disease develops and are required, but insufficient, to result in disease.[17,18]
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