Abstract
Mutational profiling, usually by targeted next-generation sequencing, is increasingly performed on patients with myeloproliferative neoplasm-associated myelofibrosis (MF), whether primary (PMF) or post-polycythemia vera/essential thrombocythemia (post-PV/ET MF). "Driver" mutations in JAK2, MPL and indels in CALR underlie the vast majority of cases of PMF and post-ET MF; the remainder (≈ 10%) lack identifiable driver mutations, but other clonal markers are usually detectable. Nearly all patients with post-PV MF carry activating JAK2 mutations. In both PMF and post-ET MF, type 1/-like CALR mutations confer a favorable prognosis. Since both type 1/-like and type 2/-like CALR mutations have essentially the same functional consequence, this is a subject of intense research. Additional, "non-driver" mutations, mostly affecting genes encoding epigenetic modifiers or spliceosome components, e.g., ASXL1, EZH2, TET2, DNMT3A, SRSF2 and U2AF1, are frequently found; some of these are associated with inferior survival and have been incorporated into prognostic models. Some mutations, e.g., IDH1/2, are relatively infrequent in chronic phase but are substantially more common in blast phase, and are now therapeutically targetable. While mutational information does not currently influence choice of drug therapy in chronic-phase MF, the presence of a "high molecular risk" genotype is now routinely taken into account for transplant decision-making.