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© Borgis - Postępy Nauk Medycznych 6/2011, s. 512-520
*Grzegorz Helbig, Sławomira Kyrcz-Krzemień
Aktualne postępy w patogenezie i leczeniu klasycznych nowotworów mieloproliferacyjnych Filadelfia-ujemnych
Recent advances in pathogenesis and treatment of classical Philadelphia-negative myeloproliferative neoplasms
Department of Hematology and Bone Marrow Transplantation, Silesian Medical University, Katowice
Head of Department: prof. Sławomira Kyrcz-Krzemień
W ostatnich kilku latach jesteśmy świadkami ogromnego postępu jaki dokonał się w zrozumieniu patogenezy nowotworów mieloproliferacyjnych (MPNs). Klasyczne nowotwory mieloproliferacyjne Filadelfia-ujemne obejmują nadkrwistość prawdziwą, nadpłytkowość samoistną i pierwotne włóknienie szpiku. Wszystkie te jednostki chorobowe wykazują podobieństwo obrazu klinicznego i zostały zgrupowane razem przez Damesheka w roku 1951. Od tego czasu, w związku z odkryciem mutacji JAK2V617F i MPL zmieniło się nasze spojrzenie na patogenezę tych chorób i doprowadziło do rewizji dotychczasowych kryteriów diagnostycznych Światowej Organizacji Zdrowia (WHO). Nowa klasyfikacja WHO została zaproponowana w roku 2008 i objęła ona niedawno opisane nieprawidłowości molekularne, zmieniając zasadniczo aktualne podejście diagnostyczne. Co więcej, mutacje te zmodyfikowały sposób monitorowania chorób, oceny efektów leczenia, a także stały się potencjalnym terapeutycznym celem dla nowych cząsteczek. W pracy przedstawiono aktualne spojrzenie na molekularną patogenezę MPNs, z podkreśleniem znaczenia nowych mutacji genetycznych. Poddano dyskusji kryteria diagnostyczne i dostępne opcje lecznicze.
In the last few years we have witnessed a great progress in our understanding of the pathogenesis of myeloproliferative neoplasms (MPNs). The classical Philadelphia-negative MPNs include polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). They were grouped together based on similar clinical phenotype by Dameshek in 1951. Since then the identification of JAK2V617F and MPL mutations has changed our view on disease pathogenesis and led to the revision of World Health Organization (WHO) diagnostic criteria for classical Philadelphia-negative MPNs. A new classification issued in 2008 incorporated these molecular abnormalities and therefore has modified the diagnostic approach. Moreover, these mutations have modified the strategies for monitoring and response assessment and they could become the potential targets for small-molecule agents. In this review we present current overview on molecular basis of MPNs including novel mutations and discuss the diagnostic criteria and therapeutic modalities.

The myeloproliferative neoplasms (MPNs) comprise a group of clonal hematopoietic stem cell disorders characterized by proliferation of one or more myeloid lineage. MPNs occur mainly in adults between 5th and 7th decade of life, and the annual incidence is estimated to be 6-10 per 100 000 population (1). The term “myeloproliferative disorders” (MPDs) was proposed in 1951 by Dameshek to encompass several disorders with similar clinical phenotype. They included polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic myelogenous leukemia (CML) and erythroleukemia (2). The last 5 years have brought a pivotal progress in our understanding of the pathogenesis of classical Ph-negative MPDs. It was associated with the identification of the specific molecular marker- the JAK2V617F point mutation, which seems to be involved in PV, ET and PMF (3). It is now clear that patients with this mutation are biologically distinct from those without the mutation and that the mutation is associated with different disease phenotype. Moreover, several novel mutations have been recently identified, but their pathogenic and prognostic relevance has not been established yet (4). The current World Health Organization (WHO) classification for hematological malignancies has incorporated the recently discovered mutations into the diagnostic approach. The term “MPDs” has been changed to “MPNs”. The WHO classification includes 8 clinical entities and it was presented in table 1 (5).
Table 1. The World Health Organization Classification of Myeloid Malignancies (5).
Myeloproliferative neoplasms (MPNs)
I Classical MPNs
Chronic myelogenous leukemia, BCR-ABL1 positive
Polycythemia veravEssential thrombocythemia
Primary myelofibrosis
II Non-classical MPNs
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia, not otherwise specified
Myeloproliferative neoplasms, unclassifiable
This current review will focus on classical Ph-negative MPNs and includes molecular basis of pathogenesis, risk stratification, diagnostic and therapeutic management.
Molecular basis for myeloproliferative neoplasms
JAK2- mutated MPNs
JAK2 is located on chromosome 9p24 and it belongs to the Janus family of non-receptor protein tyrosine kinase. Janus kinase/signal transducer and activator of transcription (JAK-STAT) signaling remains crucial for survival and normal function of hematopoietic and other cells (6). The JAK2V617F mutation is of particular relevance to MPNs including mainly PV, ET and PMF (3). The JAK2V617F results from a somatic G to T mutation involving JAK2 exon 14. It leads to nucleotide shift at position 1849 and the substitution of valine to phenyloalanine at codon 617. Mutated JAK2 causes cytokine-independent growth of cells and their hypersensitivity to cytokines (7). The JAK2V617F point mutation is found in approximately 95% of patients with PV and 40-50% of patients with ET and PMF (3, 8). Two-step model may explain the development of cells which are homozygous for JAK2 mutation. Initially, the occurrence of the JAK2V617F gives rise to a heterozygous clone which replaces normal hematopoietic cells. The second step includes mitotic recombination within cells heterozygous for the JAK2V617F with subsequent uniparental disomy. As a consequence, the daughter cells are homozygous for JAK2V617F and they replace the heterozygous clone. It may happen that myeloid cell population includes a variable proportion of JAK2 mutant alleles; it means that cells with JAK2 mutation may coexist with cells lacking this abnormality. The first step is characterized by progressive increase of mutant alleles from 0 to 50%, whereas the second step from 50 to 100% (9). The experimental studies in mouse model demonstrated that both heterozygous and homozygous JAK2 mutations induce PV-like disease phenotype, but homozygous JAK2 mutation is associated with more aggressive disease with progression to post-PV myelofibrosis (10). The JAK2V617F homozygosity is frequently seen in PV and PMF. In contrast, high mutant allele burden is rarely seen in ET (11). Homozygosity in granulocytes can be detected in 30% of patients with PV (3), but it was demonstrated in approximately 90% of colonies of hematopoietic progenitor cells derived from patients with PV whereas homozygous progenitor colonies were not observed in ET (12). This difference in the occurrence of homozygosity may result from the substantial variation in the rate of mitotic recombination among persons and the role of genetic and environmental factors determining susceptibility to mitotic recombination is very likely (11). However, it should be clearly underlined that variability in the allele burden is not sufficient to distinguish different clinical entities. It does not help us to answer the question how one mutation gives rise to three different clinical phenotypes. Moreover, there is an increasing number of evidence that the JAK2V617F is not an initiating event in MPNs and that pre-JAK2 mutated clone may exist (13). Some studies suggest that deletions of 20q and other cytogenetic abnormalities are present in about 10% of patients with MPNs and that this deletion may occur before the JAK2 mutation. It was demonstrated that deletions 20q are exclusively V617F-positive (14). In conclusion, the pathogenic role of JAK2V617F mutation requires to be better defined, especially in the light of the presence of novel mutations which may occur in patients with MPNs (4).
As it was aforementioned, JAK2 allele burden is associated with clinical phenotype and PV patients homozygous for V617F mutation have been found to have a more severe disease (15). Recently published report has demonstrated that patients with an allele burden equal or > 50% had higher white blood cell (WBC) count, greater spleen size and lower platelet count than those with less than 50% of mutant dosage. It was also proved that patients homozygous for JAK2 mutation had significantly higher risk of developing myelofibrosis (16).
JAK2 exon 12 mutations were identified in PV who were negative for JAK2V617F point mutation. Those patients presented with an isolated erythrocytosis, distinct bone marrow morphology and low serum erythropoietin level. It is noteworthy that erythroid colonies have grown from their blood samples in the absence of exogenous erythropoietin. In contrast to JAK2V617F-positive PV patients, JAK2 exon 12 mutated PV subset is often heterozygous for this mutation (17).
MPL mutations
MPL (myeloproliferative leukemia virus oncogene) located on chromosome 1p34, is the thrombopoietin receptor. MPL is highly expressed in early hematopoietic progenitors and in cells of megakaryocytic lineage. MPL is the key growth and survival factor for megakaryocytes (18). The two most common MPL mutations are W515L and W515K. They were found in about 10% of patients with PMF and in less than 10% of ET-patients lacking the JAK2V617F mutation (19). MPL-mutated ET patients are older, have lower hemoglobin concentration, higher platelet count and higher risk of arterial thrombosis (20) whereas the presence of MPL mutation in patients with PMF is associated with female gender, older age, lower hemoglobin concentration and blood transfusion dependence (21).
TET2 mutations
TET2 is located on chromosome 4q24 and its function is probably associated with epigenetic regulation of transcription (22). TET2 mutations are present in about 10-15% of patients with MPNs, including both the JAK2V617F – positive and negative cases (23). It should be highlighted that TET2 mutations may coexist with other relevant mutation e.g. KITD816V for mast cell disease (24). Moreover, it was demonstrated that TET2 mutations may precede the acquisition of a JAK2 mutation. Up-to-date studies show that the presence of TET2 mutations in MPNs do not affect survival, leukemic transformation and the risk of thrombosis (23).
Novel mutations in MPNs
Several novel mutations have been recently found in patients with MPNs:
1) ASXL1 (Additional Sex Combs-Like 1,
2) CBL (Casitas B-lineage lymphoma proto-oncogene),
3) IDH1 and IDH2 (Isocitrate dehydrogenase 1 and 2),
4) IKZF1 (IKAROS family zinc finger 1),
5) LNK,
6) EZH2.
All these mutations are rarely seen in patients with chronic phase of MPNs whereas their frequency may exceed 20% in blast transformation (tab. 2) (4).
Table 2. Novel mutations in classical myeloproliferative neoplasms (4,43) modified by authors.
MutationChromosome locationMutational frequency
JAK2 (Janus kinase 2)
JAK2V617F exon 14
9p24PV~96%; ET~55%; PMF~65%; BP~50%
JAK2 exon 129p24PV~3%
MPL (myeloproliferative leukemia virus oncogene) exon 101p34ET~3%, PMF~10%; BP~5%
TET2 (TET oncogene family member 2) exon 124q24PV~16%; ET~5%; PMF~17%; BP~17%
ASXL1 (additional sex combs-like-1) exon 1220q11.1PMF~13%, BP~18%
CBL (casitas B-lineage lymphoma proto-oncogene) exon 8/911q23.3PMF~6%
IDH1/IDH2 (isocitrate dehydrogenease) exon 42q33.3/15q26.1PV~2%, ET~1%, PMF~4%, BP~20%
IKZF1 (IKAROS family zinc finger 1)7p21BP~19%
LNK exon 212q24.12BP~10%
EZH2 (enhancer of zeste homolog 2) exons 10, 18 and 207q36.1PV~3%, PMF~7%
Legend: PV = polycythemia vera, ET = essential thrombocythemia, PMF = primary myelofibrosis, BP = blast phase.
The results including the analysis of JAK2 haplotype may suggest that hereditary component confers susceptibility to MPNs and some of above-mentioned mutations may play a role at different stages of disease evolution. A strong association between the risk of developing a JAK2V617F-positive MPNs and a germline haplotype (46/1 or GGCC) has been recently demonstrated (fig. 1) (25).
Fig. 1. Clonal evolution in myeloproliferative neoplasms (modified from 4).
2008 WHO diagnostic criteria for MPNs
General aspects

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otrzymano: 2011-03-24
zaakceptowano do druku: 2011-05-11

Adres do korespondencji:
*Grzegorz Helbig
Department of Hematology and Bone Marrow Transplantation, Silesian Medical University
Dąbrowski Street 25, 40-032 Katowice
phone: (32) 259-13-10, fax: (32) 255-49-85
e-mail: klinhem@sum.edu.pl

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