These observations have been acknowledged from a diagnostic standpoint, so that, in the absence of JAK2, CALR, or MPL mutations, the presence of one of the most frequent accompanying mutations (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, SF3B1) is now included among the major criteria for both prefibrotic-myelofibrosis (pre-PMF) and overt-myelofibrosis according to the 2016 World Health Organization (WHO) classification [23], as reported in Table 1. The gene discussed is EZH2; the disease is myelofibrosis.