Numerical gain and structural rearrangements of JAK2, identified by FISH, characterize both JAK2617V>F-positive and -negative patients with Ph-negative MPD, myelodysplasia, and B-lymphoid neoplasms

Objective Current evidence suggests that the JAK2617V>F point mutation is implicated in the pathogenesis of >90% of polycythemia vera (PV) patients, and in approximately 50% of primary myelofibrosis (PMF) and essential thrombocythemia patients. Novel JAK2 mutations were recently described in 5% to 15% of patients that are JAK2617V>F -negative. Additionally, JAK2 is reported to form fusion hybrids with three different genes. We, therefore, hypothesized that patients with 9p24 chromosomal rearrangements or patients with Philadelphia chromosome (Ph)–negative myeloproliferative disorders (MPDs), with or without +9/+9p chromosomal abnormalities, might demonstrate additional and/or cryptic JAK2 structural rearrangements. Methods Metaphase and interphase cells were retrospectively investigated from 39 patients using two JAK2 BAC fluorescence in situ hybridization (FISH) probes on archived fixed cell suspensions. Of the 39 patients, 8 had PV with chromosome 9 abnormalities, 7 had PMF/MPD showing an abnormal karyotype, 10 PV patients were cytogenetically normal, and 14 patients had 9p24 chromosomal abnormalities. Results FISH studies revealed 11 JAK2617V>F-positive patients with JAK2 numerical and structural abnormalities. Trisomy through hexasomy as well as JAK2 amplification (15–20 copies) was observed in nine patients (PV, 6; non-Hodgkin lymphoma [NHL], 1; multiple myeloma, 1; and MDS, 1), while JAK2 structural abnormalities were seen in two patients (MDS and NHL). Among the seven patients negative for JAK2617V>F mutation, two patients with MDS were observed with JAK2 rearrangements involving NF-E2 and AML1 . The status of JAK2617V>F mutation could not be determined in 13 patients, but FISH studies revealed both gain and rearrangements in three patients. They include one patient with PV and +9p with three copies of JAK2 and two patients with MDS and JAK2 relocations: one with NF-E2 , while the other patient with a TEL/ETV6 rearrangements also had tetrasomy for JAK2 . Conclusion JAK2 FISH studies revealed two types of JAK2 rearrangements among patients with Ph-negative MPDs and non-MPDs: gain and/or structural rearrangements. Gain and amplification of JAK2 was primarily observed in patients that were JAK2617V>F-positive (9 of 11), irrespective of the diagnosis, while rearrangements of JAK2 were frequently seen in patients who lacked the JAK2617V>F mutation with either MDS or AML (5 of 6). Three different JAK2 abnormalities were identified in one clone for the first time in two patients with PV. The data also identified a myriad of JAK2 rearrangements, including a novel JAK2-NF-E2 interaction, JAK2 translocation to chromosomes 3, 4, 12, 14, and 21 and detection of the previously described rare TEL/ETV6-JAK2 translocation. These observations suggest that JAK2 attracts multiple gene partners and may contribute to disease progression in patients with MDS and B-cell malignancies, while the JAK2 copy number appears to be important in pathogenesis of Ph-negative MPDs.