Over the past two centuries our understanding of myeloproliferative neoplasms has evolved from their original clinical and hematopathological observations to an increasing appreciation of the molecular mechanisms underpinning the neoplastic process and their interplay with clinical phenotype and therapy. The disorders including chronic myeloid leukemia (CML), PV, and PMF were all identified as clinical and pathological entities in the nineteenth century. ET was delineated later by Epstein and Goedel in 1934, post-PV MF was described by Hirsch in 1935, and so during the first half of the twentieth century the inter-relationship between these disorders began to be defined. Dameshek however was the first author to formally articulate the idea of a common ‘myeloproliferative’ heritage in his landmark publication of 1951 stating: “It is possible that… ‘myeloproliferative disorders’ – are all… variable manifestations of proliferative activity of the bone marrow cells, perhaps due to a hitherto undiscovered stimulus” [3]. Dameshek thus importantly postulated not only the possibility of transition between these disorders, but more interestingly a common primary mechanism for all MPNs. Dameshek’s proposal of a common underlying pathology began to bear fruition during the 1980s with growing evidence that tyrosine kinase (TK) activity provided the molecular mechanism for CML which is not formally discussed further in this chapter.

An acquired point mutation in the JAK 2 (JAK2 V617F) gene occurs in most patients with PV and almost half of those with ET or PMF and less prevalent mutations have been described in exon 12 of JAK2 and the transmembrane domain of the thrombopoietin receptor cMPL as well as others [4]. The JAK2 V617F mutation disrupts the secondary structure of the pseudokinase domain and then enables constitutive, cytokine-independent activation of signal transduction pathways, enhancing cell proliferation. The functional consequences of the mutations effecting exon 9 of CALR are not yet clear and they are beginning to be integrated into diagnostics. This has revolutionized the investigation and diagnosis of these conditions and has been incorporated into standard diagnostic pathways in a rational manner [5]. There have only been four large clinical trials, ECLAP [6], PT1 [7] and the COMFORT studies [8, 9] in these conditions to date, these have enabled hematologists to refine evidence-based management further, while current clinical trials focus upon novel agents used alone and in combination [10]. Each of the three commonest entities will now be considered in turn.