Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 2)

The etiology of PV is unknown. Although nonrandom chromosome abnormalities such as 20q, trisomy 8, and especially 9p, have been documented in up to 30% of untreated PV patients, unlike CML no consistent cytogenetic abnormality has been associated with the disorder. However, a mutation in the autoinhibitory, pseudokinase domain of the tyrosine kinase JAK2—which replaces valine with phenylalanine (V617F), causing constitutive activation of the kinase— appears to have a central role in the pathogenesis of PV.JAK2 is a member of an evolutionarily well-conserved, nonreceptor tyrosine kinase family and serves as the cognate tyrosine kinase for the erythropoietin and thrombopoietin...
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Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 2) Chapter 103. Polycythemia Vera and Other Myeloproliferative Diseases (Part 2) Etiology The etiology of PV is unknown. Although nonrandom chromosomeabnormalities such as 20q, trisomy 8, and especially 9p, have been documented inup to 30% of untreated PV patients, unlike CML no consistent cytogeneticabnormality has been associated with the disorder. However, a mutation in theautoinhibitory, pseudokinase domain of the tyrosine kinase JAK2—which replacesvaline with phenylalanine (V617F), causing constitutive activation of the kinase—appears to have a central role in the pathogenesis of PV. JAK2 is a member of an evolutionarily well-conserved, nonreceptortyrosine kinase family and serves as the cognate tyrosine kinase for theerythropoietin and thrombopoietin receptors. It also functions as an obligatechaperone for these receptors in the Golgi apparatus and is responsible for theircell-surface expression. The conformational change induced in the erythropoietinand thrombopoietin receptors following binding to erythropoietin orthrombopoietin leads to JAK2 autophosphorylation, receptor phosphorylation, andphosphorylation of proteins involved in cell proliferation, differentiation, andresistance to apoptosis. Transgenic animals lacking JAK2 die as embryos fromsevere anemia. Constitutive activation of JAK2 can explain the erythropoietin-independent erythroid colony formation, and the hypersensitivity of PV erythroidprogenitor cells to erythropoietin and other hematopoietic growth factors, theirresistance to apoptosis in vitro in the absence of erythropoietin, their rapidterminal differentiation, and their increase in Bcl-XL expression, all of which arecharacteristic in PV. Importantly, the JAK2 gene is located on the short arm of chromosome 9,and loss of heterozygosity on chromosome 9p, due to uniparental disomy is themost common cytogenetic abnormality in PV. The segment of 9p involvedcontains the JAK2 locus; loss of heterozygosity in this region leads tohomozygosity for the mutant JAK2 V617F. Over 90% of PV patients express thismutation, as do approximately 45% of IMF and ET patients. Homozygosity for themutation occurs in approximately 30% of PV patients and 60% of IMF patients;homozygosity is rare in ET. Over time, a portion of PV JAK2 V617Fheterozygotes become homozygotes, but usually not after 10 years of the disease.PV patients who do not express JAK2 V617F are not clinically different thanthose who do, nor do JAK2 V617F heterozygotes differ clinically fromhomozygotes. In general, patients who express JAK2 V617F are older than thosewho do not, but they do not have a longer duration of disease. JAK2 V617F is the basis for many of the phenotypic and biochemicalcharacteristics of PV, such as elevation of the leukocyte alkaline phosphatase(LAP) score and increased expression of the mRNA of PVR-1, aglycosylphosphatidylinositol (GPI)-linked membrane protein; however, it cannotsolely account for the entire PV phenotype. First, PV patients with the samephenotype and documented clonal disease lack this mutation. Second, IMFpatients have the same mutation but a different clinical phenotype. Third, familialPV can occur without the mutation, even when other members of the same familyexpress it. Fourth, not all the cells of the malignant clone express JAK2 V617F.Fifth, JAK2 V617F has been observed in patients with long-standing idiopathicerythrocytosis. However, while JAK2 V617F alone may not be sufficient to causePV, it is essential for the transformation of ET to PV, though not for itstransformation to IMF. Clinical Features Although splenomegaly may be the initial presenting sign in PV, most oftenthe disorder is first recognized by the incidental discovery of a high hemoglobin orhematocrit. With the exception of aquagenic pruritus, no symptoms distinguish PVfrom other causes of erythrocytosis. Uncontrolled erythrocytosis causes hyperviscosity, leading to neurologicsymptoms such as vertigo, tinnitus, headache, visual disturbances, and transientischemic attacks (TIAs). Systolic hypertension is also a feature of the red cell masselevation. In some patients, venous or arterial thrombosis may be the presentingmanifestation of PV. Any vessel can be affected, but cerebral, cardiac, ormesenteric vessels are most commonly involved. Intraabdominal venousthrombosis is particularly common in young women and may be catastrophic if asudden and complete obstruction of the hepatic vein occurs. Indeed, PV should besuspected in any patient who develops hepatic vein thrombosis. Digital ischemia,easy bruising, epistaxis, acid-peptic disease, or gas ...