JAK2 Exon 14 Deletion in Patients with Chronic Myeloproliferative Neoplasms |
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| Authors: | Wanlong Ma Hagop Kantarjian Xi Zhang Xiuqiang Wang Zhong Zhang Chen-Hsiung Yeh Susan O'Brien Francis Giles Jean Marie Bruey Maher Albitar |
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| Affiliation: | 1. Department of Hematology/Oncology, Quest Diagnostics Nichols Institute, San Juan Capistrano, California, United States of America.; 2. Department of Leukemia, M.D. Anderson Cancer Center, University of Texas, Houston, Texas, United States of America.; 3. The Cancer Treatment & Research Center (CTRC) at the University of Texas Health Science Center, San Antonio, Texas, United States of America.;University of Barcelona, Spain |
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| Abstract: | BackgroundThe JAK2 V617F mutation in exon 14 is the most common mutation in chronic myeloproliferative neoplasms (MPNs); deletion of the entire exon 14 is rarely detected. In our previous study of >10,000 samples from patients with suspected MPNs tested for JAK2 mutations by reverse transcription-PCR (RT-PCR) with direct sequencing, complete deletion of exon 14 (Δexon14) constituted <1% of JAK2 mutations. This appears to be an alternative splicing mutation, not detectable with DNA-based testing.Methodology/Principal FindingsWe investigated the possibility that MPN patients may express the JAK2 Δexon14 at low levels (<15% of total transcript) not routinely detectable by RT-PCR with direct sequencing. Using a sensitive RT-PCR–based fluorescent fragment analysis method to quantify JAK2 Δexon14 mRNA expression relative to wild-type, we tested 61 patients with confirmed MPNs, 183 with suspected MPNs (93 V617F-positive, 90 V617F-negative), and 46 healthy control subjects. The Δexon14 variant was detected in 9 of the 61 (15%) confirmed MPN patients, accounting for 3.96% to 33.85% (mean = 12.04%) of total JAK2 transcript. This variant was also detected in 51 of the 183 patients with suspected MPNs (27%), including 20 of the 93 (22%) with V617F (mean [range] expression = 5.41% [2.13%–26.22%]) and 31 of the 90 (34%) without V617F (mean [range] expression = 3.88% [2.08%–12.22%]). Immunoprecipitation studies demonstrated that patients expressing Δexon14 mRNA expressed a corresponding truncated JAK2 protein. The Δexon14 variant was not detected in the 46 control subjects.Conclusions/SignificanceThese data suggest that expression of the JAK2 Δexon14 splice variant, leading to a truncated JAK2 protein, is common in patients with MPNs. This alternatively spliced transcript appears to be more frequent in MPN patients without V617F mutation, in whom it might contribute to leukemogenesis. This mutation is missed if DNA rather than RNA is used for testing. |
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