The Philadelphia chromosome–negative myeloproliferative neoplasms (MPNs) are clonal disorders characterized by common mutations, but with distinct clinical features, treatment considerations, and prognostic outlooks.1
Identification of the JAK2 (Janus Kinase 2) V617F mutation by several groups in 2005 demonstrated that the myeloproliferative diseases are in fact clonal neoplasms.2-5
The MPNs harbor the JAK2 V617F mutation with differing frequencies; approximately 95% of polycythemia vera (PV) patients, and 50% to 60% of essential thrombocytosis (ET) and myelofibrosis patients (MF), are positive for the JAK2 V617F mutation.6
Since the discovery of the JAK2 mutation, significant progress has been made in understanding the biology of these diseases. Acquisition of the JAK2 V617F mutation leads to constitutive activation of the JAK-STAT (signal transducer and activator of transcription) signaling cascade and results in cytokine-independent signaling.2,7
Patients with MPNs, regardless of their JAK2 mutational status, have dysregulated JAK-STAT signaling.8,9
Other mutations that alter the JAK-STAT pathway have also been identified. For example, patients with JAK2 V617F-negative PV have been found to harbor JAK2 exon 12 mutation or in LNK, (also known as SH2B3), leading to sustained JAK2 signaling.10,11
LNK normally inhibits JAK signaling, and loss of function of LNK in turn results in augmented and persistent JAK-STAT signaling.12
LNK mutations are uncommon in PV and ET; however, LNK mutations have been observed in leukemic transformation in 13% of patients.13
Activating mutations in myeloproliferative leukemia virus oncogene (MPL), the receptor for thrombopoietin (TPO), which uses JAK2 for intracellular signaling, have also been found in ET and MF patients.12 Most MPL mutations occur in exon 10 on tryptophan 515, which plays an important role in the cytosolic conformation of MPL.7 The most common mutations are W515L, but others such as the W515K and the S505N have also been reported and result in TPO independent activation and downstream activation of JAK-STAT signaling.14
Recently, mutations in the calreticulin gene (CALR) were identified in the vast majority of patients without JAK2 V617F mutations in MF and ET, but not PV.15,16
The mechanism via which calreticulin leads to disease is unclear; however, it appears to mediate its effect via JAK-STAT signaling.15
This is supported by in vitro studies which demonstrate that the growth of cells expressing mutant CALR is inhibited by a JAK inhibitor.
In addition to mutations in the JAK-STAT signaling pathway, mutations in genes involved in epigenetic regulation have been observed in patients with MPN. These mutations have also been observed in other myeloid malignancies and include ten-eleven-translocation-2 (TET2), additional sex combs like 1 (ASXL1), DNA methyltransferase 3A (DNMT3A), and Enhancer of Zeste Homolog 2 (EZH2).5,17-19Diagnostic and Treatment Considerations
The discovery of the JAK2 V617F mutation improved the diagnostic accuracy of MPNs; however, this mutation by itself cannot distinguish between the MPNs, and its absence does not exclude the presence of an MPN. The World Health Organization (WHO) 2008 criteria should be followed to make an accurate diagnosis (Table 1). Testing for LNK and JAK2 exon 12 may be considered in patients who have a hemoglobin level meeting major criteria for diagnosis of PV and 1 minor criteria (ie, low EPO level), but do not have a JAK2 V617F mutation. Testing for LNK and MPL can similarly be considered in patients suspected of having ET or MF and lacking a JAK2 V617F mutation. CALR mutation testing has become commercially available, and integration of CALR mutation status into the WHO diagnostic criteria is likely in the near future.
The risk of thrombosis in PV and ET is approximately 20%; therefore, the main focus of treatment for patients with PV and ET is thrombosis prevention. To this end, most patients should take a low-dose aspirin daily.20,21 Patients with extreme thrombocytosis (>1000 × 109/L) are at risk for acquired von Willebrand syndrome and should not receive aspirin if the ristocetin cofactor activity is less than 30%.22,23
Cytoreduction can be considered for patients at high risk for thrombosis,24
with age greater than 60 years and prior episode of thrombosis being the main factors to consider its initiation.
Other factors such as leukocytosis, cardiovascular risk factors, and the presence of a JAK2 V617F mutation, although not formally part of risk stratification, can be considered in decision making as well.
Several useful models of risk stratification exist for MF: IPSS,25 DIPSS,26 and DIPSS-plus27 (Table 2). These prognostic scoring models are similar; however, the IPSS was validated for use at diagnosis only, while the DIPSS and DIPSS-plus can be used throughout the disease course. Overall survival (OS) varies significantly based on risk category, from 2 to 12 years.25