The JAK2 gene as a protagonist in chronic myeloproliferative neoplasms.

The identification of the association of a JAK2 gene mutation with chronic myeloproliferative neoplasms (cMPN) negative for BCR-ABL( has allowed significant advances in the understanding of this group of hematologic diseases. The JAK2 gene, located on chromosome 9p24, encodes the JAK2 protein which is a cytoplasmic tyrosine kinase that plays an important role in the signal transduction of various hematopoietic growth factors. The JAK2V617F mutation results in the substitution of the amino acid valine for phenylalanine in the pseudokinase domain (JH2) causing constitutive activation of the kinase domain (JH1) and hypersensitivity to protein growth factors.

Among the BCR-ABL negative cMPN cases, the JAK2617F mutation occurs at a frequency of 96% in polycythemia vera (PV), and 50% of essential thrombocythemia (ET) and chronic idiopathic myelofibrosis (MF) patients(. The association of this mutation with BCR-ABL negative cMPN has contributed to improve the diagnosis, classification and treatment of patients, in particular in respect to PV. Tefferi and Pardanani( suggested that an investigation of the JAK2V617F mutation in the peripheral blood should be integrated into the initial assessment of patients with suspected diagnosis of PV and of those of thrombocytosis of unknown cause, with thrombotic complications, including cerebral or abdominal thrombosis, and other clinical manifestations of myeloproliferative diseases.

Other less frequent mutations were also found in the JAK2 gene in JAK2V617F-negative PV patients, as well as in other myeloproliferative neoplasms. Several studies report deletions, point mutations and duplications( mainly affecting the seven highly conserved amino acid residues (F537-F547) in the JAK2 protein. PV patients positive for these mutations are often heterozygous for the mutation and are characterized by the predominance of myelopoesis, serum erythropoietin levels below normal and lower age at diagnosis(. The clinical evolution of these patients is similar to JAK2V617F-positive PV patients(.

The V617F mutation of the JAK2 gene triggers three clinical manifestations and there is evidence that genetic and additional epigenetic events contribute to the pathogenesis(. In addition, other genes, such as the MPL, TET2 and ASXL1 genes, may also be mutated with the accumulation of mutations possibly explaining the different phenotypes observed in MPN.

The MPL gene, located on chromosome 1p34, encodes the thrombopoietin receptor (cMPL). Its expression is important for growth and survival of megakaryocytes. Some mutations in this gene result in gain of function and have been associated with thrombocytosis, splenomegaly, myelofibrosis and an increased risk of thrombosis(. Mutations in the transmembrane domain of cMPL were observed in nine patients negative for the JAK2V617F mutation (MPLW515L and MPLW515K); mutations were also detected in JAK2V617F-positive patients.

The TET2 (4q24) gene has many mutations (frameshift, missense, nonsense) that are observed in JAK2V617F cMPN-positive (17%) and JAK2V617F-negative patients (7%), with mutational frequencies of approximately 16% in PV, 5% in ET, 17% in MF, 14% in post-PV MF, 14% in post-TE MF and 17% in blast-phase MPN(. The main function of the TET2 protein is the conversion of 5-methyl-cytosine to 5-hydroxymethyl cytosine; it eventually affects the epigenetic regulation of transcription.

The ASXL1 gene maps to chromosome 20q11.1 and belongs to the enhancer of trithorax and polycomb gene family. The function of this gene is believed to include dual activator/suppressor activity toward transcription and includes repression of retinoic acid receptor-mediated transcription. Mutations in this gene are associated with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CML)(. In a recent study of 300 patients with a spectrum of non-MPN myeloid malignancies, ASXL1 gene mutations were found in 62 patients (~21%): ~7% in MDS without excess blasts, 11-17% in MDS with ring sideroblasts, 31% in MDS with excess blasts, 23% in post-MDS acute myeloid leukemia (AML), 33% in CML and 30% in primary AML. It was observed that mutations of the ASXL1 gene occur in MPNs in both chronic and blast phases. In a study of 64 patients with ET (n = 35), MF (n = 11), PV (n = 10), blast-phase MPN (n = 5) and unclassifiable MPNs (n = 3), mutations of this gene in heterozygosis were identified in five JAK2V617F-negative patients (~ 8%; 3 MF, 1 ET and 1 blast-phase ET)(.

There are other reports in the literature associating gene mutations to BCR-ABL-negative cMPN. The knowledge about genotype-phenotype interaction could elucidate the molecular mechanisms and contribute to improvements in diagnosis, in the status and in the treatment of patients with ET, MF and PV.