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Delayed diagnosis leading to accelerated-phase chronic eosinophilic leukemia due to a cytogenetically cryptic, imatinib-responsive TNIP1–PDFGRB fusion gene

Leukemia volume 30, pages 1402–1405 (2016)Cite this article

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Rearrangements of the platelet-derived growth factor receptor genes (PDGFRA/B) are associated with imatinib-responsive myeloproliferative neoplasms (MPN). Together with diseases involving rearrangements of the fibroblast growth factor receptor gene FGFR1, these molecularly defined entities are grouped together by the World Health Organisation as myeloid/lymphoid neoplasms with rearrangements of PDGFRA, PDGFRB or FGFR1. Tyrosine kinase inhibitor treatment can radically alter the course of these diseases, and prompt diagnosis is important. FIP1L1–PDGFRA is the commonest rearrangement involving PDGFRA. It poses a diagnostic challenge as it is cytogenetically cryptic in most instances, involving a small interstitial deletion on chromosome 4.1 Diagnosis of this disease requires specific testing by fluorescence in situ hybridization (FISH) for the CHIC2 deletion or PCR to detect the FIP1L1–PDGFRA fusion gene. Conversely, more than 20 translocation partners of PDGFRB are known to cause MPN, often with a clinical presentation of chronic eosinophilic leukemia (CEL). All previously reported PDGFRB fusion genes in CEL/MPN have been associated with translocations involving chromosome 5, and evident on metaphase cytogenetics.2 Nevertheless, there have been cases of imatinib-responsive CEL/MPN without an identified rearrangement of PDGFRA/B. We report an unusual case of CEL/MPN due to a cytogenetically cryptic deletion involving PDGFRB.

Retrospective FISH analysis of an archived sample from 2011 confirmed that the TNIP1–PDGFRB rearrangement was present in >90% of interphase cells before the emergence of marked eosinophilia. Clonal evolution and hematological acceleration had occurred in the interim, a pattern resembling the accelerated phase of Ph-positive chronic myeloid leukemia (CML). Serial SNP array and RNA sequencing data were interrogated for aberrations acquired in association with disease acceleration using a list of 68 candidate genes known to be involved in myeloid neoplasia and advanced phase CML/MPN (Supplementary Table 1 and Supplementary Information). A known pathogenic missense mutation in DNMT3A (p.Arg882Cys) and a TET2 frameshift mutation (p.His222Thrfs*3) were present in both samples: these epigenetic mutations tend to occur early in the ontogeny of myeloid neoplasms, are associated with clonal hematopoiesis, and are often conserved at progression. Both samples also showed a stop mutation in ATM (p.Lys2756*) that has been reported as a germline pathogenic variant (COSMIC database). In the later sample there was a change in splicing pattern of TNIP1–PDGFRB with the minor in-frame transcript no longer detectable (Figure 2b). A number of additional molecular lesions were acquired at progression (Figure 2c), including deletions of ETV6 and CDKN1B,7, 8 and a missense mutation in RUNX1 (p.Arg107Gly) affecting a residue that is recurrently mutated in de novo acute myeloid leukemia and in blast phase MPN.8, 9

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Authors and Affiliations

  1. Haematology Directorate, SA Pathology, Adelaide, South Australia, Australia

    D M Ross

  2. Flinders University and Medical Centre, Adelaide, South Australia, Australia

    D M Ross

  3. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    D M Ross, C N Hahn & H S Scott

  4. Genetics and Molecular Pathology Directorate, SA Pathology, Adelaide, South Australia, Australia

    H K Altamura, C N Hahn, M Nicola, A L Yeoman, M R Holloway, S Branford, S Moore & H S Scott

  5. Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia

    C N Hahn, J Feng, A W Schreiber, S Branford & H S Scott

  6. Australian Cancer Research Foundation Genomics Facility, SA Pathology, Adelaide, South Australia, Australia

    J Geoghegan, J Feng, A W Schreiber & H S Scott

  7. School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia

    J Feng, A W Schreiber & H S Scott

  8. School of Pharmacy and Medical Science, University of South Australia, Adelaide, South Australia, Australia

    S Branford & H S Scott

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  1. D M Ross
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Correspondence to D M Ross.

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Author contributions

DMR designed the research and wrote the paper. HKA and SB performed and analyzed RT-PCR and wrote the paper. MN and SM performed and analyzed SNP array and cytogenetic studies. ALY and MRH performed the targeted massively parallel sequencing. CNH, AWS and HSS planned and interpreted RNA sequencing experiments. All authors reviewed and approved the manuscript.

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Ross, D., Altamura, H., Hahn, C. et al. Delayed diagnosis leading to accelerated-phase chronic eosinophilic leukemia due to a cytogenetically cryptic, imatinib-responsive TNIP1–PDFGRB fusion gene. Leukemia 30, 1402–1405 (2016). https://doi.org/10.1038/leu.2015.301

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