A simple model for disease initiation and progression to myelofibrosis in the Ph-negative MPNs can be proposed. Patients diagnosed with essential thrombocythemia (ET) may have either a single acquired JAK2V617F (VF) allele, an MPLS505N, MPLW515L or MPLW515K mutation (MPL), or one or more mutation(s) affecting unknown targets (collectively referred to here as an X). Duplication of the JAK2V617F allele or the acquisition of additional mutations within the affected JAK2 allele (VF*) would instead produce a polycythemic phenotype, as would the acquisition of a mono-allelic JAK2 exon 12 (ex12) mutation. The acquisition over time of one or more “driver” mutations (Y), the identities of which are currently uncertain, would initiate the transformation to myelofibrosis.