Genomic landscape of myeloproliferative neoplasms

The discovery of the Philadelphia chromosome (Ph) and BCR-ABL1 fusion gene in chronic myeloid leukaemia (CML) was a first step in understanding the genetic basis of myeloproliferative neoplasms (MPN), but it took more than 20 years until the molecular basis of Ph– MPN was unravelled with the identification of mutually exclusive mutations in JAK2, MPL, and CALR. The common effect of these mutations, activation of JAK/STAT signalling, informed the therapeutic development of JAK kinase inhibitors. Additional mutations in epigenetic modifier, mRNA splicing, and transcriptional regulator genes are present in many MPN cases. Elucidating the prognostic and functional significance of these mutations is the focus of intense ongoing studies. Given that JAK kinase inhibitors have limited impact on the mutant allele burden these additional pathways may offer much needed additional therapeutic targets. In this chapter, we discuss in detail the genetic landscape of MPN in the context of prognostication and therapy.