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.
Keywords: Myeloproliferative diseases, polycythemia vera, essential
thrombocythemia, primary myelofibrosis, mutation, diagnosis, treatment, JAK2,
TET2, Hydroxyurea, JAK inhibitor, mouse models.