Low frequency of JAK2 exon 12 mutations in classic and atypical CMPDs

The BCR-ABL negative chronic myeloproliferative disorders (CMPDs) are a group of stem cell clonal haematological malignancies characterised by abnormal proliferation and survival of one or more myeloid lineage cells. It has been proposed that they are caused by abnormalities in some signal transduction pathways mainly due to acquired somatic mutations, some of them in tyrosine kinase genes. One of the most prevalent mutations is V617F in the pseudokinase domain (JH2) coded by JAK2 exon 14. This mutation, reported in 2005, has been associated with nearly 95% of patients diagnosed of polycythaemia vera (PV) and near a half of the patients with essential thrombocythaemia (ET) and primary myelofibrosis (MF). However, the frequency of this mutation is below 20% for the remaining chronic myeloproliferative disorders and is absent in lymphoid neoplasms. JAK2V617F has been an important milestone in the knowledge of the molecular mechanisms leading to classic myeloproliferative disorders. However, there are still some patients with PV, ET and MF lacking V617F whose molecular defect is unknown. The disease in these cases could be due to other abnormalities in JAK2 or other related genes. In fact, in a few cases new point mutations have been reported, affecting also the JH2 domain, and one mutation affecting the JH1 domain [1] and reviewed in [2], some of them in other haematological malignancies. In addition, 10% of patients diagnosed of MF and some with ET show somatic activating mutations in the thrombopoietin receptor gene (MPL) inducing constitutive cytokine-independent activation of the JAK-STAT pathway.