Different expression patterns ofLGALS1andLGALS3in polycythemia vera, essential thrombocythemia and primary myelofibrosis

The Janus kinase 2 mutation, JAK2617V>F, is myeloid neoplasm-specific; its presence excludes secondary polycythemia, thrombocytosis, or bone marrow fibrosis from other causes. Furthermore, JAK2617V>F or a JAK2 exon 12 mutation is present in virtually all patients with polycythemia vera (PV), whereas JAK2617V>F also occurs in approximately half of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF). Therefore, JAK2 mutation screening holds the promise of a decisive diagnostic test in PV while being complementary to histology for the diagnosis of ET and PMF; the combination of molecular testing and histologic review should also facilitate diagnosis of ET associated with borderline thrombocytosis. Accordingly, revision of the current World Health Organization (WHO) diagnostic criteria for PV, ET, and PMF is warranted; JAK2 mutation analysis should be listed as a major criterion for PV diagnosis, and the platelet count threshold for ET diagnosis can be lowered from 600 to 450 x 10(9)/L. The current document was prepared by an international expert panel of pathologists and clinical investigators in myeloproliferative disorders; it was subsequently presented to members of the Clinical Advisory Committee for the revision of the WHO Classification of Myeloid Neoplasms, who endorsed the document and recommended its adoption by the WHO.

Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by excessive production of mature blood cells. In the majority of classic MPN--polycythemia vera, essential thrombocythemia, and primitive myelofibrosis--driver oncogenic mutations affecting Janus kinase 2 (JAK2) or MPL lead to constitutive activation of cytokine-regulated intracellular signaling pathways. LNK, c-CBL, or SOCSs (all negative regulators of signaling pathways), although infrequently targeted, may either drive the disease or synergize with JAK2 and MPL mutations. IZF1 deletions or TP53 mutations are mainly found at transformation phases and are present at greater frequency than in de novo acute myeloid leukemias. Loss-of-function mutations in 3 genes involved in epigenetic regulation, TET2, ASXL1, and EZH2, may be early events preceding JAK2V617F but may also occur late during disease progression. They are more frequently observed in PMF than PV and ET and are also present in other types of malignant myeloid diseases. A likely hypothesis is that they facilitate clonal selection, allowing the dominance of the JAK2V617F subclone during the chronic phase and, together with cooperating mutations, promote blast crisis. Their precise roles in hematopoiesis and in the pathogenesis of MPN, as well as their prognostic impact and potential as a therapeutic target, are currently under investigation.

JAK2 and MPL mutations are recurrent in myeloproliferative neoplasms (MPNs). A JAK2 mutation, primarily JAK2V617F, is almost invariably associated with polycythemia vera (PV). However, JAK2V617F also occurs in the majority of patients with essential thrombocythemia (ET) or primary myelofibrosis (PMF) as well as in a much smaller percentage of those with other MPNs. The mechanism(s) behind this one allele-multiple phenotypes phenomenon has not been fully elucidated. The issue is further confounded by the presence of marked variation in JAK2V617F allele burden among mutation-positive patients. In the current communication, we discuss potential mechanisms for phenotypic diversity among JAK2V617F-positive MPNs as well as review the current literature in regard to genotype-phenotype correlations (that is clinical correlates and prognostic significance) in the context of both the presence or absence of the mutation (ET and PMF) and its allele burden (PV, ET and PMF).