Philadelphia chromosome-negative chronic myeloproliferative neoplasms (MPN) comprise essential thrombocythemia (ET), polycythemia vera (PV), and primary myelofibrosis (PMF), including prefibrotic myelofibrosis (Pre-MF). MPNs are clonal hematopoietic neoplasms characterized by excessive proliferation of mature hematopoietic cells from one or more of the myeloid lineages. The diseases are associated with an increased risk of thrombohemorrhagic events and reduced life expectancy compared with the general population. ET and PV may progress into post-ET and post-PV myelofibrosis, and all disease entities may transform into secondary acute myeloid leukemia (sAML), which has a dismal prognosis.
The majority of MPNs are driven by somatic mutations in JAK2, CALR, or MPL that arise in the hematopoietic stem cell compartment (ie MPN phenotypic driver mutations). All three MPN phenotypic driver mutations lead to uncontrolled myeloproliferation by constitutive activation of the JAK-STAT signal transduction pathway through ligand-independent activation and hypersensitivity of type I cytokine receptors. Approximately 95-97% of patients with PV and 50-60% of patients with ET or PMF harbor a point-mutation in exon 14 of the JAK2 gene. The remaining 2-3% of PV patients carry mutations in JAK2 exon 12. CALR or MPL mutations are present in the majority of JAK2-negative ET and PMF patients. Approximately 10% of patients with MPN carry none of the three phenotypic driver mutations and are referred to as “triplenegative”.