polycythemia vera


 

  • What is polycythemia vera ?

Polycythemia vera is a disorder in the group of chronic myeloproliferative disorders (MPDs), also refered to as myeloproliferative neoplasms, that includes essential thrombocythemia (ET), primary myelofibrosis (PMF), and chronic myelogenous leukemia (CML). Polycythemia vera is an acquired clonal primary polycythemic disorder. Primary polycythemias result from abnormal intrinsic properties of erythroid progenitors that proliferate independently or excessively in response to extrinsic regulators; low serum erythropoietin is their hallmark. The most common primary polycythemia is polycythemia vera. Polycythemia vera arises from mutations in a multipotential hematopoietic stem cell, which results in an excess production of functionally normal erythrocytes, a variable overproduction of granulocytes and monocytes, and of platelets. It is usually accompanied by splenomegaly. Most patients with polycythemia vera have a somatic mutations of the Janus-type tyrosine kinase-2 gene (JAK2) that is detectable in blood myeloid cells. This mutation, JAK2 V617F, results in constitutive hyperactivity of JAK2 stemming from the loss-of-function of its negative regulatory domain. JAK2 V617F is present in virtually all cases of polycythemia vera; however, ET, MF, and, much less commonly, other hematologic neoplastic disorders are also associated with this mutation, albeit at lower frequency. As with other clonal hematologic disorders, polycythemia vera can undergo a clonal evolution to PMF (typically JAK2 V617-positive) and acute leukemia (often JAK2 V617-negative). In virtually all PV JAK2 V617F-positive patients at least some progenitors exist that became homozygous for the JAK2 V617F mutation by uniparenteral disomy acquired by mitotic recombination and the majority of these account for the erythropoietin-independent erythroid colonies detected in vitro by clonogenic burst-forming unit–erythroid assay (BFU-E). The JAK2 V617F mutation is not a cause of clonal proliferation of these disorders but is preceded by other germ-line and somatic mutation(s) that remain to be identified. Arterial and venous thromboses are the major causes of morbidity and mortality of polycythemia vera. A small proportion of patients develop secondary myelofibrosis (spent phase) and/or an invariably fatal acute leukemic transformation. Myelosuppressive therapy has been an effective mode of therapy, with drugs such as hydroxyurea, busulfan, and radioactive phosphorus useful in controlling proliferation of all blood cell lineages. Myelosuppressive therapy decreases the incidence of thrombotic complications but these drugs have variable leukemogenic potential. Newer, better-tolerated preparations of interferon such as pegylated interferon- may lead to complete hematologic remission and restoration of polyclonal hematopoiesis. Targeted therapy with JAK2 kinase inhibitors is currently being evaluated for effects on splenomegaly and splenomegaly-associated symptoms, hypercoagulability, and control of the polycythemia vera clone.

Acronyms and Abbreviations

Acronyms and abbreviations used in this chapter include: bcl-x, an antiapoptotic protein; BFU-E, burst-forming unit–erythroid; EEC, endogenous erythroid colonies; EPO, erythropoietin; ET, essential thrombocytosis; c-MPL, thrombopoietin receptor; JAK2, Janus-type tyrosine kinase 2; MPDs, myeloproliferative disorders; PFCP, primary familial and congenital polycythemia; PMF, primary myelofibrosis; PV, polycythemia vera; PRV-1, a receptor named polycythemia rubra vera 1.

Definition and History of polycythemia vera .

The term polycythemia, denoting an increased amount of blood, has traditionally been applied to those conditions in which the mass of erythrocytes is increased. In polycythemia vera (PV), an increase in the erythroid mass is frequently accompanied by an increase in neutrophils and in platelets. Chapter 56 and Table 33–2 present a classification of the polycythemias.

PV, the sole clonal form of primary polycythemia, was first described in 1892 by Vaquez.1 In 1903, Osler reviewed four cases of his own and an additional five cases from the literature. He wrote, “The condition is characterized by chronic cyanosis, polycythemia, and moderate enlargement of the spleen. The chief symptoms have been weakness, prostration, constipation, headache, and vertigo.”2 The increased proliferation of granulocyte precursors and megakaryocytes was first described by Türk in 1904.3

Cause  of polycythemia vera .

Mayo Clinic data indicate that 2.8 per 100,000 men and 1.3 per 100,000 women4 have PV, estimates that are similar to those from epidemiologic data in Sweden5; other studies and estimates indicate a higher incidence among Ashkenazi Jews.6,7 The true incidence may be higher, as many cases are asymptomatic, and thus not diagnosed. JAK2 V617F mutation testing can uncover hidden cases of PV among subjects with thrombosis or concomitant iron deficiency.

Although most patients with PV do not endorse a history of polycythemia in the family, familial incidence of the disorder is known to occur8–10 and is very likely underreported. In the familial cases, an inherited predisposition, perhaps in the form of a germ-line mutation, presumably facilitates the acquired somatic mutation(s) necessary for disease onset.9,11

Etiology and Pathogenesis  of polycythemia vera .

PV arises from the neoplastic transformation of a single normal hematopoietic multipotential cell, which provides both a selective growth and survival advantage that results in the cells produced in the clone suppressing and replacing normal polyclonal hematopoiesis. The clonal origin of PV has been demonstrated in women heterozygous for a polymorphic X-chromosome marker, glucose-6-phosphate dehydrogenase,12 as well as by more modern clonality assays (see Chap. 9).13 In each case, all hematopoietic cell lineages9,12,16 express either only one isoform of the enzyme or the X-chromosome polymorphic allele encoded by the maternal or paternal X chromosome, whereas nonhematopoietic cells are a mosaic of both enzyme types.

In vitro marrow- or blood-derived erythroid colonies of PV patients arise from both burst-forming unit–erythroid (BFU-E) precursors with normal erythropoietin sensitivity along with BFU-E that grow in the absence of erythropoietin and form so-called endogenous erythroid colonies (EEC),14,15 the latter a characteristic of PV. However, most of the BFU-E progenitors with normal erythropoietin sensitivity are also part of the PV clone.16 The fibroblasts that accumulate in the marrow of patients with PV as the disease progresses are not a part of the abnormal clone. Rather, they seem to be a response to the proliferating marrow cells, perhaps to the platelet-derived fibroblast growth factor elaborated by megakaryocytes (see Chap. 91).

Other abnormalities that have been described include (1) decreased levels of the platelet thrombopoietin receptor,17 (2) deregulation of BCL-x, an inhibitor of apoptosis,18 (3) increased expression of protein tyrosine phosphatase activity by red cell precursors,19 (4) increased messenger RNA (mRNA) levels of the PRV-1 (“a receptor named polycythemia rubra vera 1”) gene in granulocytes,20 and (5) acquired loss-of-heterozygosity of chromosome 9p as a result of uniparenteral disomy.11 This last observation led to the discovery of the Janus-type tyrosine kinase 2 (JAK2) V617F mutation located on chromosome 9p,11,21 which has improved our understanding of disease pathogenesis, improved the specificity of diagnosis and has led to an explosion of research in myeloproliferative disorders (see “JAK2 V617F Mutation” below).

There are no specific karyotypic markers occurring with high frequency in PV. Fewer than 25 percent of patients have karyotypic abnormalities at diagnosis,22–26 but the incidence rises with the increasing duration of the disease,23,27 suggesting that karyotypic abnormalities represent secondary genetic events.28

JAK2 V617F Mutation

JAK2 is present in virtually all hematopoietic cells and is essential for proliferative intracellular signaling in response to a variety of hematopoietic growth factors (see Chaps. 33 and 56). The V617F mutation was first identified in PV in 200421 and was then reported by several other laboratories.29–31 The V617F mutation is identified in virtually all patients with PV and in more than 50 percent of patients with essential thrombocytosis (ET) and myelofibrosis; rarely is it found in a minority of patients with other myeloproliferative disorders.32,33 In PV (unlike in ET), it is often in its homozygous form, at least in some of the progenitors.24,34 In some of the rare PV patients who are JAK2 V617F-negative, other JAK2 mutations have been identified in exon 12.35

Studies of families of MPD patients, in which several different MPDs occur in a single pedigree,9,36 indicate that JAK2 mutations may not be solely responsible for the disease phenotype, and may not even represent the disease-initiating event. A number of compelling lines of evidence support this conclusion. First, in familial PV, there is no clear linkage between the disease and chromosome 9p, the genetic site of JAK2, suggesting an independent germ-line predisposition to PV.11 Second, in familial PV, affected members can be either JAK2 V617F-negative or -positive.37 Third, the acquisition of the JAK2 V617F mutation is a late genetic event in PV.38 Fourth, in sporadic PV, only a proportion of clonal PV cells are JAK2 V617F-positive.34 Fifth, although the BFU-Es responsible for EEC, a hallmark of PV, are mostly JAK2 V617F-homozygous, some are heterozygous and some have a wild sequence at the JAK2 locus.34 And sixth, the acute leukemic transformation of any JAK2-positive MPDs is frequently negative for the JAK2 V617F mutation.32,39 These diverse observations strongly suggest that the somatic mutation of JAK2 gene is not the initiating or sole pathogenic process in PV.

A genomic chromosome 9p functional variant might also be relevant to the pathogenesis of the JAK2 V617F mutation. The genotypes of PV, ET, and PMF have a specific constitutional JAK2 haplotype associated with JAK2 V617F somatic mutation.40,41 This haplotype is not associated with increased JAK2 transcription or with augmented erythroid proliferation when measured in in vitro erythroid cultures.40 The acquisition of the V617F mutation of JAK2 is a late genetic event in patients with myeloproliferative disorders.38,41 This finding was determined by examining the genomic composition in individual erythroid colonies. An independent occurrence of the JAK2 V617F mutation present on different haplotypes was found, although a specific constitutional inherited JAK2 haplotype (GGCC) associated with the JAK2 V617F somatic mutation was also found in most JAK2 V617F-positive individuals and colonies.41 This GGCC haplotype of JAK2 also confers susceptibility to JAK2 exon 12 mutation-positive PV.42 These studies suggest that pre-JAK2 hypermutability events exist and that germ-line genetics play an important role in the early pathogenesis of MPDs.

In addition to the important role of JAK2 V617F and other JAK2 mutations in the etiology of PV and other MPDs, mutations in other genes may be important to the full genesis of these disorders. TET2 is a homologue of the gene originally discovered at the chromosome 10-11 translocation (TET) site in a subset of patients with acute leukemia. TET2 mutations and deletions in this gene were found in marrow cells from a significant proportion of patients with PV and other MPDs,43 and it was established that TET2 loss-of-function mutations originate in pluripotential hematopoietic stem cells but seem to favor myeloid rather than lymphoid proliferation, and that in many patients both alleles were affected. However, studies in familial PV demonstrated that TET2 mutations cannot be disease initiating, as the mutations differ among affected relatives and in some instances the TET2 mutations followed, rather than preceded, the appearance of the JAK2 V617F mutation.44