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Chronic myeloproliferative neoplasms

PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age-related clonal hematopoiesis and myeloid neoplasia

Leukemia volume 33, pages 1184–1194 (2019)Cite this article

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Abstract

Acquired uniparental disomy (aUPD, also known as copy-neutral loss of heterozygosity) is a common feature of cancer cells and characterized by extended tracts of somatically-acquired homozygosity without any concurrent loss or gain of genetic material. The presumed genetic targets of many regions of aUPD remain unknown. Here we describe the association of chromosome 22 aUPD with mutations that delete the C-terminus of PRR14L in patients with chronic myelomonocytic leukemia (CMML), related myeloid neoplasms and age-related clonal hematopoiesis (ARCH). Myeloid panel analysis identified a median of three additional mutated genes (range 1–6) in cases with a myeloid neoplasm (n = 8), but no additional mutations in cases with ARCH (n = 2) suggesting that mutated PRR14L alone may be sufficient to drive clonality. PRR14L has very limited homology to other proteins and its function is unknown. ShRNA knockdown of PRR14L in human CD34+ cells followed by in vitro growth and differentiation assays showed an increase in monocytes and decrease in neutrophils, consistent with a CMML-like phenotype. RNA-Seq and cellular localization studies suggest a role for PRR14L in cell division. PRR14L is thus a novel, biallelically mutated gene and potential founding abnormality in myeloid neoplasms.

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Acknowledgements

This work was funded by Bloodwise Specialist Programme Grants 13002 to NCPC, AC and WT, and 13042 to JB and AP. We are grateful to the Central England Haemato-Oncology Research Biobank for providing DNA from case D14.31916.

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Author notes

  1. These authors contributed equally: Andrew Chase, Andrea Pellagatti, Jacqueline Boultwood, Nicholas C. P. Cross

Authors and Affiliations

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

    Andrew Chase, Joannah Score, William J. Tapper, Feng Lin, Yvette Hoade, Catherine Bryant & Nicholas C. P. Cross

  2. Wessex Regional Genetics Laboratory, Salisbury NHS Foundation Trust, Salisbury District Hospital, Salisbury, UK

    Andrew Chase, Joannah Score, Feng Lin, Yvette Hoade, Catherine Bryant & Nicholas C. P. Cross

  3. Bloodwise Molecular Haematology Unit, Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, Oxford BRC Haematology Theme, University of Oxford, Oxford, UK

    Andrea Pellagatti, Shalini Singh, Bon Ham Yip & Jacqueline Boultwood

  4. West Midlands Regional Genetics Laboratory, Birmingham Women’s NHS Foundation Trust, Birmingham, UK

    Nicola Trim

  5. Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens, Greece

    Katerina Zoi

  6. Department of Immunology, Genetics and Pathology, Science for Life laboratory, Uppsala University, Uppsala, Sweden

    Chiara Rasi, Lars A. Forsberg & Jan P. Dumanski

  7. Beijer Laboratory of Genome Research, Uppsala University, Uppsala, Sweden

    Lars A. Forsberg

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Chase, A., Pellagatti, A., Singh, S. et al. PRR14L mutations are associated with chromosome 22 acquired uniparental disomy, age-related clonal hematopoiesis and myeloid neoplasia. Leukemia 33, 1184–1194 (2019). https://doi.org/10.1038/s41375-018-0340-5

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