JAK2V617F and the evolving paradigm of polycythemia vera

Abstract

Polycythemia vera (PV) was first described nearly 120 years ago. In the subsequent century, the clinical syndrome of PV, its natural history, its treatment, and many critical pathogenetic features of the disease were characterized. The discovery of the Janus-associated kinase - 2 mutation JAK2 V617F and the characterization of its role in myeloproliferative neoplasms have substantially changed the diagnostic paradigm for PV, and have potential to lead to new therapy and new pathogenetic insights.

The multifaceted roles of neutrophil gelatinase associated lipocalin (NGAL) in inflammation and cancer

“…ET and PV belong to the group of hematologic neoplasms termed as myeloproliferative neoplasms (MPNs) that also includes progressive myelofibrosis (PMF). PV is characterized by increase in the red cell mass (erythrocytosis) which is independent of erythropoietin (the main driver of erythropoiesis in the healthy bone marrow) while ET is a clonal stem cell disorder characterized by a tendency for an increase in platelet count and the risk of thrombotic events [248,249]. PV, like other MPNs carries a considerable risk of transformation into leukemia.…”

Structural Analysis of Janus Tyrosine Kinase Variants in Hematological Malignancies: Implications for Drug Development and Opportunities for Novel Therapeutic Strategies

“…While genetic variants within the four JAK functional domains are associated with malignancies, the most well studied focus on the pseudokinase and kinase domains as these regions are considered "hot spots" for oncogenic mutations [21] GoF mutations within these regions are associated with hyperactive JAKs and JAK/STAT signaling pathways [22]. The most notable JH2 domain genetic alterations include JAK1 V658F and the homologous JAK2 V617F mutation known to cause Polycythemia vera (PV) [23,24]. The JAK pseudokinase homologs JAK2 R683G and JAK1 R724H appear to reside within an important area as more than one alteration of these residues is related to leukemia, R683S/G, and R724H/Q/S.…”

JAK2 Variant Signaling: Genetic, Hematologic and Immune Implication in Chronic Myeloproliferative Neoplasms

“…The first studies on MPNs date from 1845, starting with the description of the first case of chronic myeloid leukemia [ 4 ]. Since then, several scholars have engaged in the analysis of the molecular mechanism of chronic myeloproliferative neoplasms, and have determined the semiological aspects of these hematological diseases by observing the signs, symptoms and clinical findings of the investigated patients [ 5 , 6 , 7 ].…”