Understanding Aberrant Signaling to Elude Therapy Escape Mechanisms in Myeloproliferative Neoplasms

SIMPLE SUMMARY: Myeloproliferative neoplasms are a group of rare disorders characterized by genetic mutations in hematopoietic stem cells and by the presence of systemic inflammation. The main driver mutations causing these diseases converge in activating the JAK2 signal transduction pathway, which plays a major role in disease onset and maintenance. Treatments based on JAK2 inhibitors ameliorate symptoms without suppressing the disease. This depends on the reactivation of JAK2 signaling and on the emergence of alternative pathways also sustained by inflammatory mediators. Molecular mechanisms at the basis of disease persistence and new therapeutic attempts to overcome them are discussed in the review. ABSTRACT: Aberrant signaling in myeloproliferative neoplasms may arise from alterations in genes coding for signal transduction proteins or epigenetic regulators. Both mutated and normal cells cooperate, altering fragile balances in bone marrow niches and fueling persistent inflammation through paracrine or systemic signals. Despite the hopes placed in targeted therapies, myeloid proliferative neoplasms remain incurable diseases in patients not eligible for stem cell transplantation. Due to the emergence of drug resistance, patient management is often very difficult in the long term. Unexpected connections among signal transduction pathways highlighted in neoplastic cells suggest new strategies to overcome neoplastic cell adaptation.