JAK2 is not a one trick pony: The JAK2V617F mutation, copy number change and rearrangement of the JAK2 gene is present among Ph-negative MPDs, MDS and B-cell neoplasms

The Myeloproliferative disorders (MPD) lacking the Philadelphia chromosome (Ph-negative) include polycythemia vera (PV), primary myelofibrosis (PMF) and essential thrombocythemia (ET). Each of these disorders is characterized by a point mutation within the JAK2 (Janus kinase 2) tyrosine kinase gene located on chromosome 9, that alters a valine to phenalanine at position 617 (V617F). The JAK2V617F-mutation is seen in over 90% of PV and in approximately 50% of PMF and ET patients. Novel JAK2 mutations were recently described in 5-15% of patients that were JAK2V617F-negative. Additionally, JAK2 fusion hybrids with three different genes (TEL/ETV6, BCR, and PCM1) have been reported. It was hypothesized that patients with 9p24 chromosomal rearrangements or a gain of chromosome 9 might demonstrate additional and/or cryptic JAK2 structural rearrangements. To test this hypothesis two JAK2 BAC FISH probes were used to retrospectively analyze 39 patients: 8 PV patients with chromosome 9 abnormalities, 7 Ph-negative MPD patients with an abnormal karyotype, 10 PV patients that were cytogenetically normal and 14 non-MPD patients with 9p24 chromosomal abnormalities. JAK2 FISH analysis revealed two major categories: (1) copy number change of JAK2 and/or (2) structural rearrangement of JAK2. An association can be suggested with the JAK2 FISH result and V617F-status: JAK2 copy number gain correlates with V617F-positive patients (9 of 9) and JAK2 structural rearrangement associates with V617F-negative patients (3 of 4). Amplification of JAK2 (6-25 copies) was noted in 2 PV patients and 2 B-cell neoplasm patients. Three genes also interacted with JAK2, which suggests that JAK2 attracts multiple fusion partners: a rare TEL/ETV6 interaction, and two novel associations with NF-E2 and AML1. Taken together these findings support the hypothesis and further suggest that JAK2 may play a role in the molecular pathogenesis of not only the MPDs, but also myelodysplastic syndromes (MDS) and rare B-lymphoid malignancies as well.