Genetics of myeloproliferative neoplasms

In the last decade, genomic studies have identified multiple recurrent somatic mutations in myeloproliferative neoplasms (MPNs). Beginning with the discovery of the JAK2 V617F mutation, multiple additional mutations have been found that constitutively activate cell-signaling pathways, including MPL, CBL, and LNK. Furthermore, several classes of epigenetic modifiers have also been identified, in patients with MPN, revealing a requirement for mutations in other pathways to cooperate with JAK-STAT pathway mutations in MPN pathogenesis. Mutations in the de novo DNA methylation protein, DNMT3A, demethylation machinery, TET2 and related IDH1/2 production of oncometabolite 2-hydroxygluterate, and polycomb complex proteins EZH2 and ASXL1 have opened new pathophysiologic clues into these diseases. The prognostic relevance of these novel disease alleles remains an important area of investigation, and clinical trials are currently underway to determine if these findings represent tractable therapeutic targets, either alone, or in combination with JAK2 inhibition.