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CYTOGENETICS AND MOLECULAR GENETICS

Germline POT1 variants can predispose to myeloid and lymphoid neoplasms

Leukemia volume 36, pages 283–287 (2022)Cite this article

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To the Editor:

Since the introduction of myeloid neoplasms with germline predisposition as a new category by the World Health Organization [1], the list of genes linked to predisposition to hematologic malignancies has continued to grow. Recently, germline variants in a shelterin complex component Protection of Telomeres 1 (POT1) have been implicated in several familial cancer syndromes, including familial chronic lymphocytic leukemia (CLL), and, more recently, a Li–Fraumeni-like multicancer predisposition, suggesting that the spectrum of POT1-related malignancies remains incompletely characterized [2,3,4,5]. A highly conserved protein, POT1, is recruited to single-stranded telomeric DNA through its interaction with ACD shelterin complex subunit and telomerase recruitment factor (TPP1), where it functions to regulate telomere length and prevent induction of DNA damage response [6]. However, the role of POT1 variants in hematologic neoplasms beyond CLL remains unknown. To explore the role of POT1 variants in hematologic neoplasms, we analyzed POT1 variants in 3323 consecutive patients who were evaluated for cytopenias or hematologic malignancies at the University of Pennsylvania.

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Fig. 1: POT1 variants in hematologic neoplasms.

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Acknowledgements

This work was supported by an Alpha Omega Alpha Carolyn L. Kuckein Student Research Fellowship to TLL and by NIH K08 HL132101 to DVB. The authors are grateful to Ping Lin for technical assistance with germline variant validation and clinical care and the Center of Personalized Diagnostics teams for patient care.

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Authors and Affiliations

  1. Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Tristan L. Lim

  2. Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    David B. Lieberman, Adam R. Davis, Ashkan Bigdeli, Adam Bagg & Jennifer J. D. Morrissette

  3. Division of Hematology-Oncology, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA

    Alison W. Loren, Ryan Hausler, Jacquelyn Powers, Elizabeth O. Hexner, Kara N. Maxwell & Daria V. Babushok

  4. Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Alison W. Loren, Jacquelyn Powers, Katherine L. Nathanson, Elizabeth O. Hexner, Kara N. Maxwell & Daria V. Babushok

  5. Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA

    Yimei Li

  6. Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Anna Raper & Katherine L. Nathanson

  7. Regeneron Pharmaceuticals Inc., Tarrytown, NY, USA

    Regeneron Genetics Center

  8. Division of Hematology-Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI, USA

    Shannon A. Carty

  9. Comprehensive Bone Marrow Failure Center, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Daria V. Babushok

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  1. Tristan L. Lim
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Contributions

TLL and DVB collected and analyzed the data, performed literature review, and wrote and revised the manuscript. DBL and JJDM established the hematologic malignancies molecular panel at the Hospital of the University of Pennsylvania and performed clinical POT1 MPS. ARD and ABa oversaw clinical hematopathology review and provided archived pathology specimens for germline validation. AWL contributed to clinical care for myeloid malignancy patients and provided leukemia and transplant expertise. RH and ABi assisted with bioinformatic analysis of POT1 variants. YL performed statistical review. JP assisted with human subjects study design and provided clinical genetics expertise. Regeneron Genetics Center performed WES for PMBB control cohort. SAC provided lymphoma expertise and assisted clinicopathological correlation of lymphoma patients. AR and KLN provided clinical genetics expertise. KLN, additionally, provided critical manuscript revisions and variant classification expertise. KNM assisted with PMBB variant analysis and provided technical expertise for FFPE DNA extraction. EOH assisted with clinicopathological correlation of myeloid malignancy patients. DVB conceived and oversaw the study. All authors assisted with data analysis and edited and approved the final version of the manuscript.

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Correspondence to Daria V. Babushok.

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The authors declare no competing interests.

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Lim, T.L., Lieberman, D.B., Davis, A.R. et al. Germline POT1 variants can predispose to myeloid and lymphoid neoplasms. Leukemia 36, 283–287 (2022). https://doi.org/10.1038/s41375-021-01335-w

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