Characterization of novel molecular targets and mechanisms in Philadelphia-negative Myeloproliferative Neoplasms

During my PhD in Clinical and Experimental Oncology at the University of Florence, I focused on the molecular underpinnings in Philadelphia-negative Myeloproliferative neoplasms (MPNs). MPNs, including Essential Thrombocythemia (ET), Polycythemia Vera (PV) and Primary Myelofibrosis (PMF), are characterized by clonal proliferation of hematopoietic progenitor cells and dysregulated production of blood cells of different lineages. MPNs are characterized by occurrence of driver mutations in JAK2V617F, CALR and MPL. The exciting discovery of new genetic abnormalities in patients with MPNs, occurred in the last decade, holds the promise for advancing our understanding of the pathogenesis of these disorders as well as improving the therapeutic management of patients. In my thesis, I will present the results of two research topics. In the first project I investigated the molecular basis of the functional crosstalk between the main signalling pathways activated by JAK2 mutation, that include the JAK/STAT and PI3K/mTOR pathways, as well how to exploit the added value of target drug combination aimed at improving efficacy, and ameliorating toxicity, of treatments in MPNs. As regard the second project, I focused on the most recently described MPN-associated driver mutations in CALR, whose function and downstream targets are still poorly known. To this end, I generated new cellular models of CALR mutations using target genomic editing and analysed the effects of mutations on cellular phenotypic traits.