Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal malignant diseases, including polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (MF) and chronic myeloid leukemia (CML). The oncogenic event underlying CML is the 9-22 translocation, resulting in the fusion protein Bcr-Abl. PV, ET and MF are MPNs Bcr-Abl negative characterized by proliferation of one or more myeloid lineages with relatively normal and effective maturation. Excessive production of mature cells involves mainly the erythroid lineage in PV, megakaryocytic lineage in ET and granulocytic and megakaryocytic lineages in MF. Common findings in MPNs patients are hepatosplenomegaly, variable predisposition to thrombotic events, bleeding and transformation to acute leukemia or bone marrow fibrosis.
Standard treatment is the use of Hydroxyurea (HU), but acetylsalicylic acid can also be indicated, especially in ET patients. Bleeding can be the therapeutic treatment of choice for patients with PV.
Recently, great progress has been achieved in understanding the molecular mechanisms of MPNs. A somatic mutation in the JAK2 gene (JAK2 V617F) was described in more than 95% of PV patients and 50-60% of ET or MF patients. JAK2V617F mutation is associated to the myeloproliferative phenotype and quickly turned into a useful clonal marker in the diagnosis and represents therapeutic target of great importance.
Additional mechanisms, such as genetic alterations in genes such as ASXL1, CBL, IDH1, IDH2, RUNX1, TET2, EZH2, LNK, among others, can play a role in MPNs etiophatogenesis. Interestingly, some of these genes were shown to be directly or indirectly implicated in regulation of DNA methylation. Although this mechanism has not been fully elucidated in MPNs, it may have therapeutic potential, as hypomethylating agents are already used in the treatment of myeloid neoplasms.
The development of new drugs is essential for the specific therapy of these diseases and preclinical tests depend on disease models. Cell lines carrying the V617F mutation are important tools for in vitro studies. Patient’s cells can also be used to study in vitro responses to different drugs. For in vivo studies, transgenic mice conditionally expressing the mutation are presented as an interesting model. Alternatively, the generation of iPS cells from patients can help understanding the pathophysiology of these diseases and testing new drugs.
Several new inhibitors for tyrosine kinases of the JAK family have been developed, such as Ruxolitinib, TG101348, Lestaurtinib and XL019. Pre-clinical tests showed different selectivity for each of the JAK family proteins and inhibition of cell proliferation. Clinical trials in phase I and phase II have been performed with some of these inhibitors and at least two of them (Ruxolitinib and TG101348) induced significant clinical response. Ruxolitinib is the first JAK2 inhibitor approved by the FDA for MF treatment. Currently other inhibitors are being developed and aim to achieve molecular remission of the disease, with a real benefit in progression and survival of these patients.