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Project abstract

Philadelphia-chromosome negative myeloproliferative neoplasms (MPNs) are heterogeneous, relatively common, hematologic disorders that include three main clinical entities, namely polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Despite these enigmatic disorders were clinically defined more than 60 years ago, there is still no effective therapy that can prevent their clonal evolution, in particular progression to acute myeloid leukemia, or that can prolong survival in the most aggressive condition, i.e., PMF. These therapeutic gaps are largely due to the fact that the molecular basis of MPNs has been recognized only five years ago with the identification of somatic gain-of-function mutation of JAK2 and MPL. However, notwithstanding these breaking-through discoveries, our current understanding of the molecular pathogenesis of MPNs is still far from being completely defined. In addition, there is a need of rapidly translating molecular acquisitions into clinical practice by developing novel diagnostic and prognostic tools and innovative therapies.

The end-points we have identified as worthwhile of the current investigation are represented by (i) the identification of somatic mutations and other abnormalities in key genetic checkpoints, i.e. epigenetic and microRNA-dependent gene expression regulation, that are responsible for the pathogenesis, phenotypic expression, and clonal evolution of MPNs and that might eventually be used as diagnostic or prognostic biomarkers; (ii) the definition of the molecular basis for hereditary predisposition to developing MPNs; (iii) the elucidation of the mechanisms by which cells of megakaryocytic and endothelial lineage modulate severity, stepwise progression and dissemination of PMF, and (iv) the development of exploratory clinical trials on the use of innovative drugs.

To reach these objectives we have designed an advanced molecular strategy that is intended to build up an integrated genetic, epigenetic, coding RNAs and microRNA portrait of involved hematopoietic progenitors and endothelial cells and with the aim of identifying and characterizing novel biomarkers and targets for therapy. The above themes define highly innovative areas of preclinical and clinical research in the field of molecular pathogenesis, diagnosis, prognostication, and treatment of MPNs.

In agreement with the aim of this call, the investigations proposed in this project will not serve as merely novel "hypothesis-generators". We will rather aim at validating a background of experimental data generated over recent years in our laboratories through the use of high-throughput analytical tools and advanced cellular and animal models, in an integrated group that involves seven units and is designed in such a way to optimize resources, knowledge and skills.

The team we assembled includes basic researchers, focusing on advanced molecular investigations, and hematologists, working on novel biomarkers, clinical models and innovative drugs and daily facing with MPN patients in their institutions. These investigators will be supported by a core of bioinformaticians for analysis of complex data, biostatisticians for the design and development of clinical trials, and hemopathologists for study of bone marrow histology. The nature and composition of the team represents a suitable platform for integrating molecular insights with clinical strategies in the spirit of "molecular medicine", with the intent to rapidly transfer experiment-generated data to the patients with myeloproliferative neoplasms by improving available diagnostic and prognostic models and performing innovative, pilot clinical trials.