Date Published: January 26, 2010
Publisher: Public Library of Science
Author(s): Valerie Ugo, Sylvie Tondeur, Marie-Laurence Menot, Nadine Bonnin, Gerald Le Gac, Carole Tonetti, Veronique Mansat-De Mas, Lydie Lecucq, Jean-Jacques Kiladjian, Christine Chomienne, Christine Dosquet, Nathalie Parquet, Luc Darnige, Marc Porneuf, Martine Escoffre-Barbe, Stephane Giraudier, Eric Delabesse, Bruno Cassinat, Alfons Navarro. http://doi.org/10.1371/journal.pone.0008893
Abstract: Myeloproliferative disorders are characterized by clonal expansion of normal mature blood cells. Acquired mutations giving rise to constitutive activation of the JAK2 tyrosine kinase has been shown to be present in the majority of patients. Since the demonstration that the V617F mutation in the exon 14 of the JAK2 gene is present in about 90% of patients with Polycythemia Vera (PV), the detection of this mutation has become a key tool for the diagnosis of these patients. More recently, additional mutations in the exon 12 of the JAK2 gene have been described in 5 to 10% of the patients with erythrocytosis. According to the updated WHO criteria the presence of these mutations should be looked for in PV patients with no JAK2 V617F mutation. Reliable and accurate methods dedicated to the detection of these highly variable mutations are therefore necessary.
Partial Text: Myeloproliferative disorders (MPDs) are hematological malignancies characterized by an accumulation of mature cells in the peripheral blood. Usually, Chronic Myeloid Leukemia (CML), a well characterized entity harbouring the recurrent t(9;22) translocation and the resulting BCR-ABL1 fusion gene, is separated from the classical MPDs such as Polycythemia Vera (PV), Essential Thrombocytemia (ET) and Primary Myelofibrosis (PMF), in which a molecular abnormality has long time been ignored. In the latter group, the recurrent V617F mutation in the exon 14 of the JAK2 gene has been identified in 2005 – and is currently a key marker for MPD diagnosis  as this mutation is present in 90%, 60% and 50% of PV, TE and PMF respectively . In 2007, novel recurrent mutations clustered in a highly conserved region in exon 12 of the JAK2 gene have been described in patients with PV or Idiopathic erythrocytosis . Exon 14 and exon 12 mutations differ by 2 main characteristics: the V617F mutation is limited to only one base change (G1846T) found in all subtypes of MPDs  as well as in splanchnic vein thrombosis  and some myelodysplastic syndromes patients . Exon 12 mutations on the other hands are extremely variable in sequence  and so far restricted to polycythaemia patients. In a recent study, using allele specific PCR, we reported the presence of JAK2 exon 12 mutations in 8 out of 24 PV patients negative for JAK2 V617F mutation, but failed to detect these mutations in patients with idiopathic erythrocytosis .
As WHO criteria for Polycythaemia Vera diagnosis include the “presence of JAK2 V617F or similar mutation„ , detection of JAK2 exon 12 mutations is of importance for the 5 to 10% of patients presenting with a suspicion of PV but with no JAK2 V617F mutation. Furthermore, pharmacological JAK2 inhibitors are, at least for some of them, equally active on V617F and JAK2 exon 12 mutations , reinforcing the need for a convenient tool to detect those mutations.