Abstract
Simple SummaryMyeloproliferative 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.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.
Highlights
Myeloproliferative neoplasms (MPNs) are clonal stem cell diseases characterized by distinct hematological and clinicopathologic features
On the base of the predominant terminally differentiated myeloid cell involved in the malignancy, MPNs are classified in different subtypes: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF)
The comprehension of aberrant signal transduction and of the mechanisms of adaptation to targeted therapies occurring in MPN cells is of extreme importance to define successful combinatorial treatments
Summary
Myeloproliferative neoplasms (MPNs) are clonal stem cell diseases characterized by distinct hematological and clinicopathologic features. Particular attention should be paid to the detection of DTA mutations (DNMT3A, TET2, and ASXL1) associated with clonal myelopoiesis, which sometimes precede the appearance of driver mutations, a more aggressive clinical course, and “overlap” syndromes with dysplastic aspects [7] These genetic discoveries and the correlation studies between the genotype and phenotype have modified clinical practice, providing new diagnostic and prognostic opportunities. These novel criteria include both the assessment of antiproliferative response and the long-term effects of the drugs These investigations measured the normalization of symptoms and signs of the disease, remission of peripheral blood counts, absence of vascular events without signs of disease progression, and bone marrow histological abnormalities. Such criteria are different in PV and in ET. JAK inhibitors could represent the foundation stone on which to build new multi-kinase inhibition strategies
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