Purpose of review: This review summarizes current understanding of the molecular genetics of polycythemia vera and essential thrombocythemia, with an emphasis on JAK2V617F pathophysiology and effect on disease phenotype.
Recent findings: JAK2V617F exerts its effects on cell growth via janus kinase-signal transducer and activator of transcription (JAK-STAT) signalling and interactions with other molecules that normally negatively regulate signalling, such as suppressor of cell signalling 3. The role of mutant JAK2 on phenotype is discussed, as not all polycythemia vera patients appear to be homozygous for the JAK2V617F mutation. Other mutations in the JAK-STAT signalling cascade are reviewed, including JAK2 exon 12, myeloproliferative leukemia virus oncogene, LNK (also known as SH2B3) mutations, and epigenetic changes in ten-eleven-translocation-2 (TET2), additional sex combs like 1 (ASXL1), PcG enhancer of zeste homolog 2 (EZH2) and DNA methyltransferase 3A (DNMT3A). Mutations associated with disease progression such as isocitrate dehydrogenase (IDH) 1, IDH2, EZH2, serine/arginine-rich splicing factor 2 (SRSF2), p53, casitas B-lineage lymphoma (c-CBL), ikaros zinc fingers (IKZF), neurofibromin 1 (NF1) and runt-related transcription factor 1 (RUNX1) are described.
Summary: In this chapter, current knowledge regarding the role of the JAK2V617F mutation on the pathogenesis and disease phenotype of polycythemia vera and essential thrombocythemia are highlighted. Other more recently recognized mutations in the JAK-STAT signalling cascade, epigenetic changes and mutations associated with disease progression are summarized.