Polycythemia vera (PV), idiopathic myelofibrosis (IMF) and essential thrombocytosis (ET) are clonal myeloproliferative disorders (MPD) that share in common increased blood production, megakaryocyte dysplasia, growth factor-independent colony formation and similar cytogenetic defects. Until recently, a dearth of molecular markers hindered analysis of the interrelationship of PV, IMF and ET. Mpl protein expression is decreased in most PV patients and the degree of impairment correlated with disease duration and extent. Impaired Mpl expression was also present in many IMF and ET patients. The recent discovery of the JAK2 V6217F mutation in PV recapitulated this behavior since JAK2 V617F was present in many classical IMF and ET patients. Importantly, JAK2 is an obligate Mpl chaperone required for Mpl surface expression (
). Since JAK2 V617F is constitutively active, we hypothesized that both its presence and gene dosage could influence Mpl expression. Therefore, we examined the concordance of the JAK2 V617F genotype and platelet Mpl protein expression in 78 PV, 13 IMF and 82 ET patients, using allele-specific, real-time PCR screening of granulocyte DNA for JAK2 V617F and quantitative densitometry for platelet Mpl with a cutoff of ≤ 60% for reduced and ≥ 120% for overexpression. JAK2 V617F prevalence was 91% in PV (40% homozygous), 46% in IMF (66% homozygous) and 41% in ET (none homozygous). JAK2 V617F-negative patients (7 PV, 7 IMF and 58 ET) were indistinguishable clinically from JAK2 V617F-positive patients. Mean disease duration was similar for homozygous JAK2 V617F (11 years, range 1–25) and heterozygous JAK2 V617F (8 years, range 1–22) PV patients. Mean disease duration was also similar for JAK2 V617F-positive (7.5 years, range 1–18) and JAK2 V617F-negative (6 years, range 1–22) ET patients. Mean Mpl expression was 31% in PV patients (range 1–227, reduced in 89%), 7% in IMF (range 1–22, reduced in 100%) and 72% in ET (range 1–246, reduced in 52%). Of the JAK2 V617F-positive patients, mean platelet Mpl was 27% in PV (range 1–86%, reduced in 92%), 5% in IMF (range 1–11%, reduced in 100%) and 38% in ET (range 1–127%, reduced in 81%). JAK2 V617F genotype significantly inversely correlated (p<0.004) with platelet Mpl expression: in JAK2 V617F homozygotes, mean platelet Mpl expression was 12% (range 1–44, 100% reduced); in JAK2 V617F heterozygotes, mean Mpl expression was 35% (range 1–127, 86% reduced), while in JAK2 V617F-negative patients, mean Mpl was 82% (range 1–246%, 44% reduced). JAK2 V617F-negative PV and IMF patients had either markedly reduced Mpl (8 patients, mean 6%) or markedly elevated Mpl (2 patients, mean 200%). In ET, JAK2 V617F-positive patients had reduced platelet Mpl (38% of normal, range 1–127%) compared to JAK2 V617F-negative patients (92% of normal, range 1–246%) (p=0.004). However, JAK2 V617F-negative ET patients were heterogeneous; 42% had reduced, 24% normal and 33% elevated platelet Mpl expression. These data indicate that JAK2 V617F expression and gene dosage directly influence platelet Mpl expression in PV, IMF and ET. Less commonly however, impaired Mpl expression, often marked, also occurred in the JAK2 V617F-negative setting, suggesting that other genetic or epigenetic lesions can create the same molecular abnormality. We conclude that Mpl protein expression abnormalities, whether associated with JAK2 V617F or not, provide a common denominator for the MPD phenotype. JAK2 V617F genotype does not necessarily predict MPD phenotype, but the degree of Mpl reduction does.
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