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Recurrent cyclin D2 mutations in myeloid neoplasms

Leukemia volume 31, pages 2005–2008 (2017)Cite this article

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Philadelphia-negative neutrophilic leukemias—atypical chronic myeloid leukemia (aCML), chronic neutrophilic leukemia (CNL), MDS/MPNu (myelodysplastic/myeloproliferative neoplasm, unclassifiable), and MPNu (myeloproliferative neoplasm, unclassifiable)—are rare hematologic neoplasms characterized by leukocytosis, a hypercellular bone marrow comprised predominantly of granulocytic cells, absence of the Philadelphia chromosome (t(9;22); BCR-ABL1), and absence of PDGFRA/B or FGFR1 gene rearrangements. Occasional cases of CNL1 and MDS/MPNu,2 as well as a majority of aCML cases, exhibit non-specific cytogenetic abnormalities3 or the JAK2 V617F mutation,4 revealing their clonal nature. The primary genetic basis of these leukemias was unknown until recent work by Maxson et al.,5 which highlighted mutations in CSF3R as key leukemogenic drivers in ~60% of patients with aCML or CNL. Subsequent studies found CSF3R mutations in a majority of patients with CNL and only in a minority of patients with aCML,6 with parallel studies of aCML revealing the presence of recurrent SETBP1 and ETNK1 mutations.7, 8 Despite these discoveries, knowledge of the full genetic landscape of Philadelphia-negative neutrophilic leukemias remains incomplete. To identify and characterize additional mutations contributing to the pathogenesis of these malignancies, we performed whole exome sequencing (WES) on 116 Philadelphia-negative neutrophilic leukemia samples (Supplementary Materials and Methods).

We identified 4/116 samples harboring mutations in CCND2, the gene encoding the cell cycle regulator cyclin D2. Of these four samples, one was pathologically confirmed as MPNu, while another was confirmed as MDS/MPNu (Supplementary Table 1). Interestingly, all mutated samples harbored variants in codon 281, with three samples possessing a P281S variant and the other carrying a P281L variant (Supplementary Table 1). These changes appeared to occur as heterozygous mutations and were present only in patients lacking CSF3R mutations, with one sample (13-00010) harboring a known pathogenic SETBP1 variant (I871T), and another (14-00247) possessing an SRSF2 P95H variant. Two out of four samples harbored a TET2 mutation (other observed mutations in Supplementary Table 2). All mutations with additional available DNA were confirmed by Sanger sequencing (Supplementary Figure 1).

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Acknowledgements

We thank the OHSU Massively Parallel Sequencing Shared Resource for their assistance with whole exome sequencing, and members of the Druker and Tyner laboratories for thoughtful and critical discussions. V.K. was supported by the Howard Hughes Institute Medical Research Fellows Program. C.A.E. and C.E.T. are funded through a Howard Hughes Medical Institute Investigator award to BJD JEM is supported by an ASH Scholar Award and the NCI (4R00CA190605-03). DKEV was supported by the National Science Foundation Graduate Research Program (DGE-1448072). JWT was supported by the Leukemia and Lymphoma Society, the V Foundation for Cancer Research, the Gabrielle’s Angel Foundation for Cancer Research, and the National Cancer Institute (5R00CA151457-04; 1R01CA183947-01). BJD is an Investigator of the Howard Hughes Medical Institute. This work was supported in part by an award from the St Baldrick’s Foundation (280290).

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Authors and Affiliations

  1. Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA

    V Khanna, C A Eide, C E Tognon, J E Maxson, B Wilmot, D Bottomly, S McWeeney, D K Edwards V, B J Druker & J W Tyner

  2. Howard Hughes Medical Research Fellows Program, Howard Hughes Medical Institute, Portland, OR, USA

    V Khanna

  3. Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, USA

    V Khanna

  4. Division of Hematology and Medical Oncology, Oregon Health and Science University, Portland, OR, USA

    C A Eide, C E Tognon, J E Maxson, D K Edwards V, B J Druker & J W Tyner

  5. Howard Hughes Medical Institute, Portland, OR, USA

    C A Eide, C E Tognon & B J Druker

  6. Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR, USA

    J E Maxson, D K Edwards V & J W Tyner

  7. Division of Bioinformatics and Computational Biology, Department of Medical Informatics and Clinical Epidemiology, Oregon Health and Science University, Portland, OR, USA

    B Wilmot, D Bottomly & S McWeeney

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  1. V Khanna
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Correspondence to J W Tyner.

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Khanna, V., Eide, C., Tognon, C. et al. Recurrent cyclin D2 mutations in myeloid neoplasms. Leukemia 31, 2005–2008 (2017). https://doi.org/10.1038/leu.2017.195

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