The saga of JAK2 mutations and translocations in hematologic disorders: pathogenesis, diagnostic and therapeutic prospects, and revised World Health Organization diagnostic criteria for myeloproliferative neoplasms

Prodromal myeloproliferative neoplasms: The 2008 WHO classification

“…In this context, it is important to mention that the mandate of the PVSG was to investigate the natural history of PV, establish diagnostic guidelines, and conduct clinical trials by formulating uniform entry criteria for PV and ET to exclude other causes of erythrocytosis and thrombocytosis [55,56]. According to the recently published reports, peripheral blood screening for JAK2V617F is currently the preferred initial test for evaluating patients with persistent erythrocytosis [3,4]. Accordingly, the proposal to the WHO included a lowering of the diagnostic hemoglobin level in men to >17 g/dl and in women to >15 g/dl, if associated with a sustained increase of 2 g/dl from baseline that cannot be attributed to correction of iron deficiency [1].…”

“…It has been generally recognized that the main issue of the 2008 established diagnostic guidelines for chronic myeloproliferative neoplasms (MPN) proposed by several international working groups to the World Health Organization (WHO) emphasizes a close consensus of clinical laboratory findings with morphological features and moleculargenetic data [1][2][3][4]. Contrasting a number of previous [5][6][7] and recently published classification systems [8,9], the rationale was the generation of an useful interface between all these different parameters that are not only aimed to increase diagnostic sensitivity and specificity, but also provides easily applicable algorithms for routine clinical practice [2,3,10].…”

“…Contrasting a number of previous [5][6][7] and recently published classification systems [8,9], the rationale was the generation of an useful interface between all these different parameters that are not only aimed to increase diagnostic sensitivity and specificity, but also provides easily applicable algorithms for routine clinical practice [2,3,10]. In this regard, diagnostic criteria for the classical Philadelphia chromosome-negative (Ph 12 ) MPN as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), have been substantially changed by inclusion of the JAK2V617F mutation status and similar activating mutations [3,4]. As a consequence clinicians are becoming more and more aware that a positive expression of these markers including Exon 12 and MPLW 515L/K mutations [3,4,8,[11][12][13][14][15][16][17] may discriminate reactive from neoplastic conditions even in initial-early stage MPN.…”

“…In this regard, diagnostic criteria for the classical Philadelphia chromosome-negative (Ph 12 ) MPN as polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), have been substantially changed by inclusion of the JAK2V617F mutation status and similar activating mutations [3,4]. As a consequence clinicians are becoming more and more aware that a positive expression of these markers including Exon 12 and MPLW 515L/K mutations [3,4,8,[11][12][13][14][15][16][17] may discriminate reactive from neoplastic conditions even in initial-early stage MPN. On the other hand, because JAK2V617F mutation was reported in virtually all patients with PV and up to 50% of cases with ET and PMF, its presence alone does not help in subclassification of MPN nor does a negative finding definitively exclude a MPN [3,4].…”

“…As a consequence clinicians are becoming more and more aware that a positive expression of these markers including Exon 12 and MPLW 515L/K mutations [3,4,8,[11][12][13][14][15][16][17] may discriminate reactive from neoplastic conditions even in initial-early stage MPN. On the other hand, because JAK2V617F mutation was reported in virtually all patients with PV and up to 50% of cases with ET and PMF, its presence alone does not help in subclassification of MPN nor does a negative finding definitively exclude a MPN [3,4]. In this context, it is important to realize that JAK2V617F and related mutations are late events in the molecular evolution of MPN [11].…”