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Cytogenetically cryptic ZMYM2-FLT3 and DIAPH1-PDGFRB gene fusions in myeloid neoplasms with eosinophilia

Leukemia volume 31, pages 2271–2273 (2017)Cite this article

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More than 70 tyrosine kinase (TK) fusion genes have been identified in myeloid neoplasms as a consequence of reciprocal translocations or other genomic rearrangements. These TK fusions are generally primary drivers of myeloproliferation and important therapeutic targets, as well as being major criteria for the diagnosis of specific disorders. For example, chronic myeloid leukemia is defined by the presence of BCR-ABL1, and myeloid/lymphoid neoplasms with eosinophilia are defined by fusions involving PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2.1 Other TK fusions have been described in patients with various subtypes of myeloproliferative neoplasms (MPN) or myelodysplastic syndrome/MPN. Most of these individuals have pronounced eosinophilia,2 but occasional cases have other phenotypes, such as polycythemia vera (PV) or systemic mastocytosis.2, 3 Apart from FIP1L1-PDGFRA, which is formed by a small deletion at 4q12,4 TK fusions are almost always associated with visible karyotypic abnormalities. Despite their apparent prominence in the literature, TK fusions are in fact uncommon and the pathogenesis of the majority of MPN with eosinophilia (MPN-eo) remains unexplained. Some TK fusion-negative cases test positive for KIT D816V or JAK2 V617F, whereas others are positive for mutations in a range of genes associated with myeloid disorders, such as TET2, ASXL1, EZH2 and SETBP1.5, 6, 7 We hypothesized that hitherto undetected cryptic TK fusion genes may drive MPN-eo, as well as other disorders, such as JAK2-unmutated PV.

We used RNAseq to search for TK fusion genes in cases with MPN-eo or hypereosinophilia of unknown significance with a normal karyotype (n=14), PV with low or normal erythropoietin levels that tested negative for MPN phenotype driver mutations (n=6) and cell lines that were derived from MPN or myelodysplastic syndrome patients that had transformed to acute myeloid leukemia (F-36P, ELF-153, FKH-1, GDM-1, SKK-1, SKM-1). RNA extraction, polyA+ RNA-Seq library preparation, stranded RNAseq protocol and 100 bp paired-end sequencing was performed with multiplexing for a minimum of 75 million reads/sample using a HiSeq 2000 (Illumina, Little Chesterford, UK). Bowtie and TopHat-Fusion were used to align reads, resolve splice junctions, identify and filter potential TK fusions as previously described.8 Confirmation and screening of fusions were performed by reverse transcriptase-PCR and Sanger sequencing (Supplementary Table 1).

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Acknowledgements

This work was supported by grant 13002 to NCPC from Bloodwise and the Deutsche José Carreras Leukämie-Stiftung e.V. (grant no. DJCLS R 13/05).

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Authors and Affiliations

  1. Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Mannheim, Germany

    M Jawhar, N Naumann, A Fabarius, G Metzgeroth, W-K Hofmann & A Reiter

  2. Faculty of Medicine, University of Southampton, Southampton, UK

    M Knut, J Score, M Ghazzawi, A Chase, W Tapper & N C P Cross

  3. Department I of Internal Medicine, University Hospital of Cologne, Cologne, Germany

    B Schneider, K-A Kreuzer & M Hallek

  4. Department of Human and Animal Cell Lines, Leibniz-Institute DSMZ, German Collection of Microorganisms and Cell Cultures, Braunschweig, Germany

    H G Drexler

  5. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK

    J Chacko & L Wallis

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  1. M Jawhar
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Correspondence to N C P Cross.

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Competing interests

NCPC has received honoraria and research support from Novartis and honoraria from Pfizer. AR has received honoraria and research support from Novartis. The other authors declare no conflict of interest.

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Supplementary Information accompanies this paper on the Leukemia website

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Jawhar, M., Naumann, N., Knut, M. et al. Cytogenetically cryptic ZMYM2-FLT3 and DIAPH1-PDGFRB gene fusions in myeloid neoplasms with eosinophilia. Leukemia 31, 2271–2273 (2017). https://doi.org/10.1038/leu.2017.240

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