We pay particular attention to the newly identified JAK2V617F mutation in polycythaemia vera, essential thrombocythaemia and idiopathic myelofibrosis and deal with disease heterogeneity and putative additional molecular mechanisms.
We show that transplantation of JAK2(V617F)-transduced bone marrow into BALB/c mice induces MPD reminiscent of human PV, characterized by erythrocytosis, granulocytosis, extramedullary hematopoiesis, and bone marrow fibrosis, but not thrombocytosis.
The lack of thrombocytosis suggests that additional events may be required for JAK2 V617F to cause ET, but qualitative platelet abnormalities induced by JAK2V617F may contribute to the hemostatic complications of PV.
Discovery of a constitutively activating point mutation of the Janus kinase 2 (JAK2) receptor-associated tyrosine kinase in patients with polycythemia vera (PV) and other BCR/ABL-negative myeloproliferative disorders prompted many groups around the world to examine diverse subsets of patients with myeloid diseases for the prevalence of the JAK2V617F mutation and its clinical and pathological associations.
Recently, activating mutations of the intracellular cytokine-signaling molecule JAK2 have been identified in > 90% of patients with PV and in 50% of those with IMF and ET.
Solely, ET JAK2V617F in megakaryocytes is associated with a PV-like phenotype, and at least in one patient, the JAK2 mutation was exclusively acquired within the megakaryocytic lineage.
A single point mutation (Val617Phe) was identified in JAK2 in 42 (73.7%) of 57 patients with PV, 40 (58.8%) of 68 with ET, and eight (66.7%) of 12 with MMM.
We set-up a multiplex real-time polymerase chain reaction assay followed by capillary electrophoresis, designed to simultaneously screen the two main genetic lesions associated with CMDs, i.e. the BCR-ABL fusion characteristic of chronic myeloid leukemia and the JAK2V617F mutation that characterises polycythaemia vera and a proportion of cases of essential thrombocythemia and idiopathic myelofibrosis.
The JAK2V617F mutation is a frequent genetic event in the three classical Philadelphia-chromosome negative chronic myeloproliferative disorders (Ph(neg.)-CMPD), polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF).
Other mutations of putative pathogenetic relevance in MPDs include: JAK2V617F in PV, ET, and PMF; JAK2 exon 12 mutations in PV; MPLW515L/K in PMF and ET; KITD816V in SM; FIP1L1-PDGFRA in CEL-SM; rearrangements of PDGFRB in CEL-CMML and FGFR1 in stem cell leukemia-lymphoma syndrome; and RAS/PTPN11/NF1 mutations in JMML.
In vitro expansion of PV erythroid progenitors and differentiated dendritic cells resulted in a decrease of the frequency of JAK2(V617F) allele compared with granulocytes or CD235(+) erythroid progenitors.
Using quantitative polymerase chain reaction (PCR), we found that high levels of JAK2 617V>F in PV correlate with increased granulocytes and high levels of hemoglobin and endogenous erythroid colony formation.
Our results indicate that JAK2 mutation might be linked to Lu/BCAM modification and increased RBC adhesiveness, which may be a factor favoring thrombosis in PV.
Catastrophic intra-abdominal thrombosis can result from a variety of prothrombotic states, including polycythemia vera and essential thrombocythemia, both of which are frequently associated with an acquired mutation (V617F) in the JAK2 gene.
JAK2 617V>F positive polycythemia rubra vera maintained by approximately 18 stochastic stem-cell divisions per year, explaining age of onset by a single rate-limiting mutation.
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.