Somatic Mutations in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPN) include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPN are characterized by clonal proliferation of myeloid progenitors leading to erythrocytosis, thrombocytosis, or leukocytosis, and risk of hemorrhagic and thrombotic events, as well as myelofibrosis and blast transformation. The discovery of somatic mutations in MPN, namely JAK2 V617F, JAK2 exon 12, MPL, and CALR mutations, has permitted a more specific approach to diagnosis and treatment. The prevalence of JAK2 V617F mutations is higher than 95% in PV, 50%-75% in ET and 40%-75% in PMF. JAK2 exon 12 mutations are specific of PV. A 20%-30% of patients with ET and PMF present a CALR mutation. The screening of mutations strengthens the diagnosis of MPN since 97% of MPN have at least 1 somatic mutation. Interestingly, different mutations grant different phenotype and prognosis. Of particular importance, CALR mutations grant a favorable prognosis in ET and PMF, while ASXL1 mutations confer a poorer outcome. In fact, the use of CALR/ASXL1 status for the prognostication of patients has increased clinical value and is now suggested for guidance of therapy in PMF. The increasing importance of mutations in the management of MPN warrants a more frequent revision of current diagnostic criteria and prognostic models and a better understanding of the mechanisms leading to MPN subset differentiation.