INTRODUCTION — An overview of the four classic myeloproliferative neoplasms (MPN): polycythemia vera, essential thrombocythemia, primary myelofibrosis, and chronic myeloid leukemia will be presented here. Detailed information on each of these disorders is presented separately.
CLASSIFICATION OF HEMATOLOGIC MALIGNANCIES — The hematopoietic pluripotent stem cell is capable of both self-renewal and stepwise differentiation into either the lymphoid or myeloid lineage (which appears to be determined stochastically) . Thus, during normal hematopoiesis, there exists a cellular hierarchy headed by a stable population of pluripotent stem cells that generate lineage-specific progenitors, which differentiate into the various types of mature blood cells . Effective hematopoiesis is facilitated by interactions of hematopoietic growth factors, various receptors, and the bone marrow microenvironment.
An operational classification of hematologic malignancies distinguishes lymphoid from myeloid neoplasms (table 1 and table 2); in turn, each of these categories is classified as either acute or chronic, depending on the proportion of morphologically and immunophenotypically immature precursors (blasts) in the bone marrow or peripheral blood. Thus, the myeloid hematologic malignancies are divided into acute myeloid leukemia (AML; bone marrow or peripheral blood blasts of 20 percent or more) and the chronic myeloid disorders (bone marrow or peripheral blood blasts less than 20 percent). However, in the presence of certain recurrent cytogenetic abnormalities (eg, t(8;21), inv(16)), a diagnosis of AML is made regardless of the blast count.
The chronic myeloid disorders — The chronic myeloid disorders encompass several clinicopathologic entities. Conceptually, they can be organized into those that display significant morphologic dysplasia in the erythroid and/or granulocyte lineages (the myelodysplastic syndromes and the myelodysplastic/myeloproliferative overlap neoplasms) or those that do not display dysplastic changes (myeloproliferative neoplasms) [3,4]:
●Myelodysplastic syndromes (MDS) are characterized by cellular dysplasia, variable degrees of peripheral blood cytopenias, and bone marrow hyperplasia (or less often, hypoplasia) . The paradox of proliferative bone marrow together with peripheral blood cytopenias in MDS may be explained by increased intramedullary myeloid precursor cell apoptosis .
●Myeloproliferative neoplasms (MPN), unlike MDS, usually exhibit terminal myeloid cell expansion in the peripheral blood . MPNs include polycythemia vera, essential thrombocythemia, chronic myeloid leukemia (CML), primary myelofibrosis, chronic neutrophilic leukemia, and other less well defined entities such as chronic eosinophilic leukemia, not otherwise categorized.
●Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) include disorders that manifest both dysplastic and proliferative features. These include chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, atypical CML (aCML, BCR::ABL1 negative), MDS/MPN with ring sideroblasts and thrombocytosis, and unclassifiable MDS/MPN.
Clonal studies in the chronic myeloid disorders — Genetic and enzyme studies based upon X-chromosome inactivation patterns have revealed a multipotent progenitor cell origin for the neoplastic clone in both MDS  and MPN . The clonal process may develop at different progenitor cell levels in individual patients, and the clonal progenitor cell may or may not involve T and B lymphocytes . (See 'Potential significance' below.)
Studies using refined methods of X-linked DNA analysis have demonstrated polyclonal hematopoiesis in some patients with essential thrombocythemia and monoclonal hematopoiesis in healthy elderly women . However, JAK2 V617F mutation analysis has revealed that patients with "polyclonal" essential thrombocythemia might also display the mutation . Therefore, X-chromosome-based clonal assays might not be adequate in detecting a minor clonal population against a polyclonal background.
These observations underline the heterogeneity between individuals with MPNs, and raise the possibility that monoclonal hematopoiesis may antedate rather than follow the development of mutations (described below) that are associated with MPNs or MDS. (See 'Potential significance' below and "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis".)
Familial disease — Familial clustering of polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) has been well described [13-16]. Abnormalities that have been described in such families include mutations in the JAK2, MPL, CBL, TET2, CALR, or RBBP6 genes, most often somatic but occasionally germline [16-18].
●In a study of 458 adult patients with apparently sporadic disease, familial involvement was noted in 8.7, 6.0, and 8.2 percent of those with PV, ET, or PMF, respectively .
●In a population-based study from Sweden involving 11,039 patients with MPN, their 24,577 first degree relatives had significantly increased risks of PV (relative risk [RR] 5.7), ET (RR 7.4), and unclassifiable MPN (RR 7.5), and a borderline increased risk of CML (RR 1.9; 95% CI 0.9-3.8) .
Patients with familial disease developed similar complications and disease evolution as those with sporadic disease. Age distribution between parent and offspring and telomere length shortening provided evidence for disease anticipation in one study . However, this age difference between parent and offspring was not seen in the large population-based study from Sweden .
Presence of the JAK2 mutation does not appear to represent the genetic predisposing factor [13,19-23], although it might indicate which family members are at higher risk of developing one of the MPNs at a future date . (See "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera", section on 'Familial PV'.)
Diagnostic criteria for PV and ET may not pertain to children, owing to known mutations in several other genes (eg, hereditary mutations of the erythropoietin receptor, thrombopoietin, MPL genes) in families with polycythemia or ET presenting in childhood . (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Familial essential thrombocythemia' and "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera", section on 'Other disorders'.)
THE CLASSIC MYELOPROLIFERATIVE DISEASES
Diagnosis — Among the four classic MPNs, only chronic myeloid leukemia (CML) is genetically characterized by reciprocal translocation between chromosomes 9 and 22; this t(9;22) translocation is associated with a shortened chromosome 22 (the Philadelphia chromosome) in 95 percent of the cases . In the remaining cases, t(9;22) can be demonstrated by either fluorescence in situ hybridization (FISH) or reverse transcriptase polymerase chain reaction techniques for detection of BCR::ABL1. While cytogenetic abnormalities are common in primary myelofibrosis (approximately 30 percent at time of diagnosis) and uncommon in essential thrombocythemia (approximately 5 percent at time of diagnosis), no specific cytogenetic abnormality has been associated with MPNs other than CML . (See "Molecular genetics of chronic myeloid leukemia".)
The discovery that JAK2 mutations are found in virtually all patients with polycythemia vera (PV) and approximately 50 percent of those with either essential thrombocythemia (ET) or primary myelofibrosis (PMF) has refined diagnostic criteria in the classic MPNs [4,28-31]:
●PV is considered to be present when an otherwise unexplained increased hematocrit/red blood cell mass is accompanied by the presence of a JAK2 mutation (table 3). (See "Clinical manifestations and diagnosis of polycythemia vera".)
●PMF (agnogenic myeloid metaplasia, chronic idiopathic myelofibrosis) is characterized by the presence of bone marrow fibrosis that cannot be attributed to another myeloid disorder such as CML, PV, ET, or MDS (table 4 and table 5). However, it should be noted that the morphological phenotype of PMF can exist without the presence of overt bone marrow fibrosis (ie, prefibrotic PMF). (See "Pathogenetic mechanisms in primary myelofibrosis" and "Clinical manifestations and diagnosis of primary myelofibrosis".)
●ET is a diagnosis of exclusion, representing clonal or autonomous thrombocytosis not classifiable as PV, PMF, CML, or MDS (table 6). (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia".)
Within the context of the MPNs, an elevated red cell mass is specific for PV. Occasionally both CML and MDS may present with either isolated thrombocytosis suggesting ET , or with bone marrow fibrosis suggesting myelofibrosis [33,34]. As a result, the diagnostic evaluation of patients with suspected MPN should always include cytogenetic studies and careful morphologic examination to exclude the presence of t(9;22) (CML) and dysmyelopoiesis (myelodysplastic syndrome [MDS]), respectively.
Although most of the chronic myeloid disorders are classifiable as MDS, CML, PV, ET, or PMF, some are difficult to categorize and may be referred to as MPN-unclassifiable or MDS/MPN-unclassifiable [35,36]. In general, BCR::ABL1 is specific to CML, but rare patients expressing both BCR::ABL1 and a JAK2 mutation have been described [37,38].
Complications — The major complications of the MPNs include thrombosis, bleeding, or evolution to acute myeloid leukemia (AML) or a fibrotic phase of the disease.
Malignancies and disease transformation — As a group, the MPNs are predisposed to clonal evolution and disease transformation to AML, MDS, or fibrotic phase of the disease [39,40]. The propensity to transform into AML differs among the subgroups, being highest for CML (greater than 90 percent in the absence of effective therapy) and least for ET (less than 5 percent). Patients with PV have an approximately 10 and 25 percent chance of transforming into a myelofibrotic stage at 10 and 25 years of follow-up, respectively . (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Transformation to acute leukemia' and "Prognosis and treatment of polycythemia vera and secondary polycythemia", section on 'Hematologic complications'.)
The risk for disease transformation in the MPNs is influenced by both disease-related and treatment-related factors. Disease-related factors associated with a higher risk of progression to myelofibrosis or AML include mutations of CALR, epigenetic regulators, splicing factors, and RAS signaling molecules [42-46].
The effect of treatment on disease transformation was assessed in a nested case-control study of a nationwide cohort of 11,039 subjects with PV, ET, and PMF that included 153 who developed AML, 9 who developed MDS, and 242 matched controls. Results included :
●Forty-one of the 162 patients with MPN who developed AML or MDS (25 percent) had never been exposed to alkylating agents, radioactive phosphorus (32P), or hydroxyurea, indicating a substantial propensity of the MPNs to undergo disease transformation in the absence of cytoreductive treatment.
●Increased risk of developing AML/MDS was associated with high exposures to 32P (odds ratio [OR] 4.6; 95% CI 2.1-9.8) and alkylating agents (OR 3.4; 95% CI 1.1-10.6), but not with exposure to hydroxyurea (OR for the highest exposure 1.3; 95% CI 0.5-3.3).
●Risk of AML/MDS was increased in patients receiving two or more cytoreductive treatments (OR 2.9; 95% CI 1.4-5.9).
Results of a Danish population-based cohort study indicated an increased risk of development of both hematologic and non-hematologic malignancies in patients with PV, ET, and CML :
●The standardized incidence ratios for hematologic malignancies were 5.0, 3.8, and 5.2 for ET, PV, and CML, respectively.
●The standardized incidence ratios for non-hematologic malignancies were 1.2, 1.4, and 1.6 for ET, PV, and CML, respectively.
The frequency of lymphoproliferative neoplasms in two series of patients with MPNs was 1.3 to 1.6 percent, with a cumulative risk of LPN development between 1 and 3 percent at 5 to 10 years of follow-up, corresponding to a standardized incidence ratio >4 [49,50]. This risk was higher in those harboring the JAK2 V617F mutation and was increased as much as 12-fold for the development of chronic lymphocytic leukemia. It has not been definitively shown that these two entities, when coexisting, arise from a common hematopoietic stem cell .
Despite these observations, it remains uncertain if disease transformation or development of secondary neoplasms in MPN is affected by treatment of any kind.
Treatment of MPN-associated acute leukemia — Leukemic/blast phase transformation (LT) of an MPN is difficult to treat. Current consensus is to treat with curative intent using an AML-like induction chemotherapy, followed by allogeneic hematopoietic cell transplantation (HCT). However, few reports demonstrate the value of such an approach. Two examples are discussed below:
In a single center report of 75 patients with MPN-associated LT, the two-year overall survival (OS) was 15 percent . Selected patients with a reasonable fitness level achieved long-term control after chemotherapy with curative intent, followed by allogeneic HCT. Two-year OS were as follows for the following subgroups:
●Treatment with non-curative regimens – 3 percent
●Complete remission following chemotherapy with curative intent – 15 percent
●Complete remission following chemotherapy with curative intent, followed by HCT – 47 percent
A retrospective report from the European Group for Blood and Marrow Transplantation included results from 57 patients with an initial diagnosis of PV or ET who underwent myeloablative allogeneic HCT following the development of AML. Results included the following :
●At the time of transplant only 22 percent were in complete remission from AML.
●At a median follow-up of 13 months, estimated three-year OS and nonrelapse mortality were 28 and 29 percent, respectively. The high rate of relapse of AML following HCT (53 percent) contributed to the low OS noted in this group of patients.
●Adverse prognostic features included age >55 years at the time of transplant and the use of an unrelated donor.
Thrombosis and bleeding — Another biologic complication shared among the MPNs is the risk of thrombohemorrhagic complications, which is most pronounced in PV and ET .
●Thrombotic complications include arterial and venous thromboses, and microcirculatory disorders such as erythromelalgia (picture 1) and visual and neurologic symptoms . Serial in vivo activation of leukocytes, vascular endothelium, platelets, and the coagulation system have been postulated as possible causes of these complications [56-60]. Erythromelalgia is associated with platelet consumption and platelet thrombi in the microvasculature; both the shortened platelet survival and symptoms can be ameliorated by aspirin, but not by heparin or warfarin, suggesting that a prostaglandin synthase product in platelets plays an important role .
●Rates of arterial and venous thromboses are elevated in all categories of MPN, in all age groups, and equally in men and women, according to a population-based study of 9429 Swedish patients . The incidence of thrombosis is highest shortly after diagnosis. Compared with the control population, the incidence of arterial and venous thromboses in patients with MPNs in the first three months after diagnosis was increased three- and 10-fold, respectively; the hazard ratios declined in subsequent years, but remained elevated throughout the five years of observation.
●Major thrombotic events can occur in patients who otherwise have few clinical and laboratory features of PV. Examples include splanchnic vein thrombosis (eg, Budd-Chiari syndrome, portal, splenic, or mesenteric vein thrombosis) , in whom the ensuing portal hypertension and hypersplenism may mask the increase in blood cell counts [64-69]. PV should be suspected in patients with these diagnoses, particularly women under the age of 45. (See "Etiology of the Budd-Chiari syndrome", section on 'Myeloproliferative disorders'.)
●Bleeding episodes are usually mild, with spontaneous bleeding primarily occurring in patients with high platelet counts (eg, those who develop acquired von Willebrand disease); both quantitative and qualitative changes in platelet function may contribute to bleeding [55,70]. (See "Acquired von Willebrand syndrome", section on 'Myeloproliferative neoplasms including ET'.)
Because of the variable risks of blastic transformation and thrombosis-associated deaths, OS in the MPNs ranges from a "near-normal" life expectancy in patients with ET to a median of less than five years in patients with PMF .
Other complications — A Danish population-based cohort study revealed an increased risk of osteoporotic bone fractures in patients with MPNs when compared with the general population, with a step-wise increasing pattern from ET (hazard ratio [HR] 1.19) to PV (HR 1.82) to CML (HR 2.67) . The cause is unknown, although the presence of comorbidities (eg, smoking, alcohol-related diagnoses) did not explain the increased fracture risks.
Symptoms and quality of life — In addition to the major complications noted above (eg, thrombosis, hemorrhage, evolution to AML), patients with MPN also suffer from symptoms that may interfere with their quality of life. These issues were evaluated in an Internet-based symptom survey of 1179 patients with MPN . The frequency of self-reporting for the following complaints were as follows:
●Fatigue – 81 percent
●Pruritus – 52 percent
●Night sweats – 49 percent
●Bone pain – 44 percent
●Fever – 14 percent
●Weight loss – 13 percent
Among each of the MPNs, fatigue was the most common complaint, being present in 85, 72, and 84 percent of those with PV, ET, and PMF, respectively. Approximately one-third of the respondents needed assistance with activities of daily living and 11 percent reported MPN-related medical disability.
A Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) has been devised and prospectively validated as an assessment tool for patients with MPNs embarking on clinical trials . This form has been modified to include an abbreviated version (the MPN-SAF Total symptom score) that focuses on the most representative and clinically relevant MPN symptoms, which include the following 10 items: fatigue, early satiety, abdominal discomfort, inactivity, concentration problems, night sweats, itching, bone pain, fever, and weight loss [75,76]. However, there is heterogeneity of symptoms within each MPN subtype, sometimes independent of disease features or prognosis .
Role of hematologic growth factors — The role of hematologic growth factors in the development and/or propagation of the clonal process in MPN remains undefined. Growth factor independence of the clonal process in MPNs is suggested by the following observations:
●MPNs are characterized by spontaneous hematopoietic colony formation (ie, without the addition of a growth factor) .
●Erythropoietin (EPO) levels in patients with PV are appropriately downregulated, and studies have not revealed genetic mutations involving the EPO receptor . Overexpression of Bcl-xL (an inhibitor of apoptosis) in erythroid precursors from patients with PV provides a possible explanation for how these cells can grow autonomously in the absence of EPO . (See "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera".)
●The clonal process in ET appears to be independent of thrombopoietin (TPO) signaling, because molecular lesions have not been identified in TPO and mutations of the TPO receptor (MPL) are seen in only approximately 5 percent of patients with ET . Serum TPO concentrations in patients with ET are either normal or above normal, suggesting defective feedback regulation . Consistent with this observation, Mpl expression in platelets and megakaryocytes is reduced in patients with ET .
●TPO receptor (MPL) expression in platelets and megakaryocytes is absent or markedly reduced in PV, suggesting that proliferation of platelets in PV is independent of TPO (as it is in ET) .
While growth factors have not been implicated in the neoplastic process, they are believed to contribute to the pathogenesis of bone marrow fibrosis associated with the MPNs. In an experiment in mice, lethal irradiation was followed by grafting of bone marrow cells infected with a retrovirus carrying murine TPO cDNA . The initial phase was characterized by marked elevations in the platelet and white blood cell counts followed by a syndrome of bone marrow fibrosis, extramedullary hematopoiesis, hepatosplenomegaly, anemia, and leukemic transformation. The PMF-like illness is thought to be mediated by overproduction of transforming growth factor (TGF)-beta by megakaryocytes, which has also been implicated in human myelofibrosis .
Gene expression profiling and microRNAs — Gene expression profiling (GEP) and mutational analysis were used to characterize 55 patients with PV, ET, or PMF . The major findings in this study included the following:
●A GEP consistent with activated signaling through the JAK-STAT pathway was seen in all MPN patients, regardless of clinical phenotype (ie, PV, ET, or PMF) or mutational status (ie, JAK2 V617F or Calreticulin [CALR] mutation), consistent with a shared mechanism of transformation among the MPNs.
●Transcriptional profiling discriminated subsets of MPNs based on JAK2 V617F allele burden and on the presence of CALR, ASXL1, and TET2 mutations, suggesting that these patterns might explain phenotypic differences among the three MPNs.
The role of microRNAs in the MPNs is unclear; reviews of this subject are available [88,89].
Mutations in PV, ET, and PMF
Overview — The most commonly mutated genes in PV, ET, and PMF are JAK2, CALR, and MPL; estimates of their frequency follow [46,90-95]:
●PV – 100 percent JAK2 mutations (exon 14 or 12)
●ET – 60 to 65 percent JAK2 mutation, 20 to 25 percent CALR mutation, 3 percent MPL mutation
●PMF – 60 to 65 percent JAK2 mutation, 20 to 25 percent CALR mutation, 7 percent MPL mutation
Genomic characterization of 2035 patients with these MPNs found that one of these three mutations was the sole abnormality in 45 percent . Approximately 8 to 10 percent of PMF cases and 10 to 15 percent of ET cases lack conventional mutations in JAK2, CALR, and MPL (ie, "triple negative" MPNs). Studies employing whole exome sequencing have revealed that a minority of these cases have non-canonical mutations in JAK2, MPL, and other genes (some of which are discussed below) [46,96,97]. (See 'Other mutations' below.)
JAK2 mutations — Mutations of the tyrosine kinase Janus kinase 2 (JAK2), a gene found on the short arm of chromosome 9 (9p), appear to account for hypersensitivity of hematopoietic progenitor cells in MPNs to growth factors and other cytokines [98-106]. (See "Clinical manifestations and diagnosis of polycythemia vera", section on 'JAK2 mutations' and "Molecular pathogenesis of congenital erythrocytoses and polycythemia vera", section on 'JAK2 mutations'.)
JAK2 mutations arise preferentially on a common constitutional JAK2 haplotype (variously called 46/1 or GGCC), which is found in approximately 50 percent of normal persons [107-109]. JAK2 mutations are most abundant in erythroid and myeloid cells, although its presence in other cell lines (eg, lymphoid cells of B cell, T cell, and NK cell lineages, endothelial cells) is debated [57,110-115]. In one study of 115 patients with MPN, the JAK2 mutation, when present, was found slightly more often in platelets than in granulocytes (72 versus 62 percent) .
Mutation in exon 14 of JAK2 substitutes a bulky phenylalanine for a conserved valine at position 617 in the JH2 or pseudokinase domain (Val617Phe, V617F), which negatively regulates the kinase domain, causing cytokine-independent activation of JAK-STAT, other pathways implicated in erythropoietin (EPO) receptor signaling, and the phosphatidylinositide-3 kinase (PI3K) pathway (which regulates apoptosis) [117,118].
Incidence — A single gain-of-function point mutation in JAK2 in either exon 14 or 12 has been identified in virtually all patients with PV, and in 60 to 65 percent of those with ET and PMF [103,119-121]. The presence of JAK2 mutations in EPO-independent erythroid colonies links this mutation to growth factor hypersensitivity . Further study of JAK2 and the STAT pathway might allow for a more reliable classification/diagnostic system for MPNs and a more complete understanding of their pathophysiology [46,117,123-126].
A discussion of refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T), a myelodysplastic variant with myeloproliferative features and a high frequency of the JAK2 V617F mutation, is found elsewhere. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)
As an example, the JAK2 V617F mutation has been found only infrequently in other chronic myeloid disorders (eg, MDS, chronic myelomonocytic leukemia, systemic mastocytosis, chronic neutrophilic leukemia, unclassifiable MDS/MPN), but has been seen in some patients with acute myeloid leukemia following a prior MPN, strengthening the specific association between this mutation and the classical BCR::ABL1-negative MPNs (ie, PV, ET, PMF) [127-131]. Of interest, one strain of transgenic mice highly expressing this JAK2 mutation developed phenotypes closely resembling ET and PV, and developed PMF-like symptoms as they aged .
The finding of dysregulated tyrosine kinase (TK) activity also suggests a possible therapeutic approach to these disorders, via the use of small molecule JAK2 TK inhibitors [133-139], similar to those successfully employed in CML and other malignancies. (See "Cellular and molecular biology of chronic myeloid leukemia", section on 'BCR-ABL1 signaling'.)
Allele burden — The mechanism(s) through which this single gene mutation is associated with such phenotypic variability is unknown, although gene dosage effects (allele burden), occurrence of other genetic events, and genetic instability have been postulated . As an example, many patients with PV and PMF harbor homozygous JAK2 mutations, whereas most cases of ET appear to be heterozygous for this mutation [46,141]. In one study, larger numbers of homozygous-mutant erythroid colonies were associated with older age and male sex in PV, but only with female sex in ET, potentially explaining the preponderance of men with PV but of women in ET .
Documenting the presence of a JAK2 mutation and the allele burden may help to distinguish PV from secondary polycythemia, and ET from reactive thrombocytosis [143,144]. Mutation analysis can be done with equal sensitivity and specificity using either peripheral blood granulocytes or bone marrow . Such testing may serve as a marker to measure measurable residual disease (MRD; also referred to as minimal residual disease) following treatment with interferon or hematopoietic cell transplantation [146,147], and stratify the risk of thrombosis  or evolution to post-PV or post-ET myelofibrosis . (See "Prognosis and treatment of essential thrombocythemia", section on 'Risk stratification'.)
●A number of studies have found the JAK2 V617F mutation in a high percentage of patients with Budd-Chiari syndrome, many of whom had negative results from standard testing for one of the MPNs. It has been suggested that patients with this syndrome, in whom no underlying disorder can be identified, be tested for this mutation. (See "Etiology of the Budd-Chiari syndrome", section on 'Myeloproliferative disorders'.)
●In patients with PMF undergoing hematopoietic cell transplantation, achievement of negativity for JAK2 V617F was associated with a decreased incidence of relapse . (See "Myelofibrosis (MF): Management of primary MF and secondary MF".)
●In a prospective study of 26 patients with PV and 21 with ET, treatment with hydroxyurea was able to achieve a partial molecular response in 57 percent, as indicated by a significant decrease in JAK2 V617F allele load after 36 months of treatment . In contrast, a control group that was not treated with hydroxyurea showed a slight increase in allele load over this same period of time.
Calreticulin (CALR) mutations — Calreticulin (also known as calregulin) is a Ca++ binding protein localized primarily in the endoplasmic reticulum (ER), but it is also found in the nucleus, cell membranes, and extracellular matrix . The encoding gene (CALR) is located on chromosome 19p13.2 and contains nine exons. The C-terminal region of wild-type calreticulin includes both a calcium-binding domain and an endoplasmic reticulum retention motif.
CALR mutations have been observed in approximately 70 percent of patients with ET or PMF who do not carry a mutation in either JAK2 or MPL, and have only rarely been observed in patients with PV; all known CALR mutations involve frameshift mutations within exon 9 that generate a mutant protein with a novel C-terminus [90,91,94,152]. Normal functions of calreticulin include proper folding of newly synthesized glycoproteins within the ER and modulating calcium homeostasis [153,154]; mutations associated with ET and PMF disrupt the calcium-binding and endoplasmic reticulum retention domains. These mutations appear to alter the protein's function, resulting in cytokine-independent growth and activation of JAK/STAT signaling that is sensitive to pharmacologic JAK2 inhibition [90,155]. Mutant CALR interacts directly with the thrombopoietin receptor (MPL) resulting in constitutive activation of MPL and downstream signaling molecules in the JAK/STAT pathway [156-158]. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Genetic features'.)
More than 50 different mutations in CALR have been described, but a 52 base pair deletion (type 1) or a 5 base pair insertion (type 2) account for more than 80 percent of mutations . In a study of 1027 patients with ET, both CALR variants were associated with higher platelet and lower hemoglobin and leukocyte counts than those with mutant JAK2 ; the platelet count was significantly higher in those with the type 2 mutation than in those with the type 1 mutation, suggesting differential effects of CALR variants on thrombopoiesis.
MPL mutations — Activating mutations of MPL, which encodes the thrombopoietin receptor (TPO-R), have been found in patients with familial ET. (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia", section on 'Familial essential thrombocythemia' and "Biology and physiology of thrombopoietin", section on 'Familial thrombocythemia'.)
However, such mutations have not been commonly observed in patients with MPNs, and their overall clinical significance is unclear [160,161].
●In one large study, novel somatic activating mutations MPL (W515L and W515K) were found in approximately 5 percent of patients with PMF, 1 percent of those with ET, and in none of the patients with PV .
●In a second study, MPL mutations were seen in 16 of 143 patients (11 percent) with ET and 3 of 32 patients (9 percent) with PMF .
●In a study of 603 patients with PMF, mutant MPL was detected in 8.1 percent and JAK2 V617F in 58 percent. Multivariate analysis disclosed no significant difference in OS or leukemia-free survival between MPL-mutated, JAK2-mutated, and JAK2/MPL-mutated groups .
●In a study of 508 subjects with MPNs, an MPL exon 10 somatic mutation was found in 7 percent. Unlike the finding in those with the JAK2 V617F mutation, MPL mutations were not significantly associated with the JAK2 GGCC haplotype, suggesting a different genetic background for these two molecular lesions .
Other mutations — A large number of other somatic mutations have been found in patients with MPNs, but their contribution to the pathogenesis of MPNs is largely undefined [165-167]. Some of these mutations may be "drivers" of the malignant process, while others may be a consequence of genomic instability or related to clonal hematopoiesis of indeterminate potential (CHIP) [168-170]. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonal hematopoiesis of indeterminate potential (CHIP)'.)
Besides JAK2, CALR, and MPL, the genes that are most commonly mutated in PV, ET, and PMF are [46,165-167,170-176]:
●TET2 (TET oncogene family member 2)
●ASXL1 (Additional sex combs 1)
●DNMT3A (a DNA methyltransferase)
●CBL (Casitas B-lineage lymphoma)
●TP53 (Tumor protein p53)
●PPMD1 (p53–inducible protein phosphatase 1)
●SRSF2 (Splicing factor, arginine/serine-rich 2)
●U2AF1 (Splicing factor U2AF1)
●KMT2C/MLL3 (Lysine N-methyltransferase 2C/mixed-lineage leukemia protein 3)
●SF3B1 (Splicing factor 3b 1)
●NFE2 (Nuclear factor E2)
●EZH2 (histone H3 lysine 27 methyltransferase)
●LNK (Src homology 2 B3, SH2B3)
●IDH 1/2 (Isocitrate dehydrogenase 1/2)
●IKZF1 (IKAROS family zinc finger 1)
Mutations of some of these genes have been associated with transformation to AML or other malignancies:
●In one study of 422 patients with PV and ET, a polymorphism in the DNA repair gene XPD showed a strong association with both leukemic transformation (OR 4.9; 95% CI 2.0-12) and the development of non-myeloid malignancies (OR 4.2; 95% CI 1.5-12) .
●A study of 22 genes in 53 patients with leukemic transformation after an MPN identified mutations in some of the above genes (eg, JAK2, TET2, ASXL1, IDH1/2, MPL) as well as in the serine/arginine-rich splicing factor 2 (SRSF2) .
●Using next generation sequencing in 197 MPN patients, somatic mutations in one or more of 104 specified genes were found in 90 percent, with 37 percent carrying somatic mutations in genes other than JAK2 V617F and CALR . The presence of ≥2 somatic mutations reduced overall survival and increased the risk of transformation to acute myeloid leukemia. A similar observation was made in a separate study of mutations in five prognostically-detrimental genes in 797 patients with PMF; in this study, median survivals were 12.3, 7.0, and 2.6 years, respectively for those with no, one, or two or more mutations in ASXL1, EZH2, SRSF2, IDH1, or IDH2 .
Potential significance — The significance of JAK2, MPL, CALR, and other mutations in the genesis of the MPNs as well as their relative roles in determining disease phenotype, leukemic transformation, and the level of involvement of stem cells in these disorders are unclear at present [113,114,164,180-185]. However, data from integrated genomic analyses suggest that patients with PV, ET, or PMF, regardless of diagnosis or JAK2 mutational status, are characterized by a distinct gene expression signature with upregulation of JAK-STAT target genes, demonstrating the central importance of this pathway in the pathogenesis of the MPNs . (See 'Gene expression profiling and microRNAs' above.)
In some patients with MPNs, clonal myelopoiesis may antedate acquisition of JAK2, MPL, or CALR mutations, and the latter mutations may be acquired in a lympho-myeloid progenitor cell [46,113,186-188]. Mutations of TET2, DNMT3A, SF3B1, ASXL1, and other genes are often seen in older patients with MPNs and in individuals with CHIP, but their pathogenetic and prognostic relevance to development of MPNs is uncertain [87,171,189-192]. (See "Clonal hematopoiesis of indeterminate potential (CHIP) and related disorders of clonal hematopoiesis", section on 'Clonal hematopoiesis of indeterminate potential (CHIP)'.)
However, initial data suggest that the order in which these mutations are acquired impacts the clinical phenotype. This was illustrated in a study that determined the genetic evolution of MPNs (PV, ET, or PMF) with mutations in both JAK2 and TET2 . Neoplasms that acquired the JAK2 mutation prior to the TET2 mutation were more likely to present at a younger age, have clinical features of PV, and develop thrombosis. In contrast, the presence of a TET2 mutation prior to the acquisition of a JAK2 mutation may alter the impact of the JAK2 mutation, perhaps through methylation-based silencing of genes that are normally expressed.
Homozygosity or heterozygosity for a JAK2 mutation, the presence of other mutations (MPL, CALR, or TET2 mutations), the order in which the mutations occurred, the balance between the sizes of their respective clones (ie, allele burden), MPL receptor expression, loss of heterozygosity in TP53, and/or other host genetic variations (eg, single nucleotide polymorphisms  or specific haplotypes within the JAK2 gene) may determine predisposition to development of one of these mutations, the clinical phenotype (eg, degree of thrombocytosis, leukocytosis, and erythrocytosis, splenic size, pruritus, transformation to myelofibrosis or AML) [141,159,169,187,195-209], as well as the response to treatment .
However, at this time one can make the following conclusions concerning these mutations :
●The diagnostic approach to the MPNs must now include evaluation of the mutation status of JAK2, MPL, and CALR. Such information will also be of value for determining prognosis as well as individual risk assessment.
●Quantitative assays for the JAK2 V617F mutation are preferred because they enable better estimation of allele burden (ie, lower in ET, higher in PV, and highest in PV which has evolved into myelofibrosis) as well as molecular monitoring of treatment response [92,211]. (See 'Allele burden' above.)
We suggest performing mutation analysis at the time of diagnosis, but this decision may be influenced by available resources and by patient choice. This evaluation may be postponed until a time of disease progression when therapeutic decisions include the possibility of hematopoietic cell transplantation.
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Polycythemia vera (PV) (The Basics)")
●Description – Myeloproliferative neoplasms (MPN) are clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid lineages, peripheral blood cytosis with effective maturation, bone marrow hypercellularity/fibrosis, and splenomegaly (table 1).
The four classic MPNs are: chronic myeloid leukemia, polycythemia vera, essential thrombocythemia, and primary myelofibrosis. Other MPNs include chronic eosinophilic leukemia; chronic neutrophilic leukemia; and MPN, unclassifiable.
●Complications – MPNs are associated with variable risks for thrombohemorrhagic complications, progression to acute leukemia, and bone marrow failure from myelofibrosis and/or ineffective hematopoiesis. (See 'Complications' above.)
●Genetics – Chronic myeloid leukemia is associated with the Philadelphia chromosome (Ph), an acquired reciprocal translocation between chromosomes 9 and 22.
Most other MPNs (ie, Ph-negative MPNs) are associated with acquired mutations of JAK2, CALR, or MPL. Other mutations may be present, but it is uncertain if they are drivers of the malignancy, consequences of genomic instability, and/or related to clonal hematopoiesis of indeterminate potential (CHIP). (See 'Mutations in PV, ET, and PMF' above.)
●Chronic myeloid leukemia (CML) – Cells of the granulocytic lineage are the predominant proliferative component. CML is characterized by t(9;22), which creates a BCR::ABL1 rearrangement that encodes the constitutively active tyrosine kinase, BCR::ABL1.
Most cases of CML present in the relatively indolent chronic phase (CP); some patients present with advanced disease (accelerated phase [AP] or blast crisis [BC]), which are characterized by rising blast percentages with systemic symptoms and/or progressive splenomegaly. Most cases of advanced disease arise from progression of CP CML during treatment with a BCR::ABL1 tyrosine kinase inhibitor (TKI). (See "Clinical manifestations and diagnosis of chronic myeloid leukemia".)
●Polycythemia vera (PV) – PV is characterized by increased red blood cell proliferation. Virtually all patients carry JAK2 V617F, a somatic gain-of-function mutation (table 3).
Most cases present in a polycythemic phase with elevated hemoglobin/hematocrit. Some patients present in a spent phase, with cytopenias (including anemia) in association with post-polycythemic myelofibrosis, ineffective hematopoiesis, and increasing splenomegaly. (See "Clinical manifestations and diagnosis of polycythemia vera".)
●Primary myelofibrosis (PMF) – PMF is characterized by proliferation of abnormal megakaryocytes and granulocytes in bone marrow, a leukoerythroblastic blood picture, splenomegaly, and bone marrow fibrosis. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)
A prefibrotic phase of PMF (table 4) may precede fibrotic stages (table 5), which are associated with marrow fibrosis and extramedullary hematopoiesis. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)
●Essential thrombocythemia (ET) – ET is manifest as sustained thrombocytosis with megakaryocytic proliferation.
ET is a diagnosis of exclusion, with clonal autonomous thrombocytosis not classifiable as PV, PMF, CML, or myelodysplastic syndrome (MDS) (table 6). (See "Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia".)
ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
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