Insights into the molecular genetics of myeloproliferative neoplasms

The molecular biology of the BCR-ABL1-negative chronic myeloproliferative neoplasms (MPNs) has witnessed unprecedented advances since the discovery of the acquired JAK2 V617F mutation in 2005. Despite the high prevalence of JAK2 V617F in polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), and the common finding of dysregulated JAK-STAT signaling in these disorders, it is now appreciated that MPN pathogenesis can reflect the acquisition of multiple genetic mutations that alter several biologic pathways, including epigenetic control of gene expression. Although certain gene mutations are identified at higher frequencies with disease evolution to the blast phase, MPN initiation and progression are not explained by a single, temporal pattern of clonal changes. A complex interplay between acquired molecular abnormalities and host genetic background, in addition to the type and allelic burden of mutations, contributes to the phenotypic heterogeneity of MPNs. At the population level, an inherited predisposition to developing MPNs is linked to a relatively common JAK2-associated haplotype (referred to as '46/1'), but it exhibits a relatively low penetrance. This review details the current state of knowledge of the molecular genetics of the classic MPNs PV, ET, and PMF and discusses the clinical implications of these findings.