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CHRONIC MYELOPROLIFERATIVE NEOPLASMS

Recurrent germline variant in ATM associated with familial myeloproliferative neoplasms

Leukemia volume 37, pages 627–635 (2023)Cite this article

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Abstract

Genetic predisposition (familial risk) in the myeloproliferative neoplasms (MPNs) is more common than the risk observed in most other cancers, including breast, prostate, and colon. Up to 10% of MPNs are considered to be familial. Recent genome-wide association studies have identified genomic loci associated with an MPN diagnosis. However, the identification of variants with functional contributions to the development of MPN remains limited. In this study, we have included 630 MPN patients and whole genome sequencing was performed in 64 individuals with familial MPN to uncover recurrent germline predisposition variants. Both targeted and unbiased filtering of single nucleotide variants (SNVs) was performed, with a comparison to 218 individuals with MPN unselected for familial status. This approach identified an ATM L2307F SNV occurring in nearly 8% of individuals with familial MPN. Structural protein modeling of this variant suggested stabilization of inactive ATM dimer, and alteration of the endogenous ATM locus in a human myeloid cell line resulted in decreased phosphorylation of the downstream tumor suppressor CHEK2. These results implicate ATM, and the DNA-damage response pathway, in predisposition to MPN.

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Fig. 1: Molecular and clinical characteristics of the familial and unselected MPN cohorts.
Fig. 2: The filtering strategies and germline variants identified in the unbiased approach.
Fig. 3: In silico prediction of the effect of Leucine to Phenylalanine substitution in the position 2307 on ATM function.
Fig. 4: The effect of ATM L2307F on ATM and CHEK2 phosphorylation at steady state and after ionizing radiation.

Data availability

All data generated or analyzed during this study are either included in this published paper and its supplementary materials or will be made available upon request.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH), Heart, Lung and Blood Institute grant K08HL138142 (EMB), K08HL136894 (LPG), R01HL156144 (LPG), and in part by the Intramural Research Program of the National Heart, Lung, and Blood Institute of the National Institutes of Health (JG and CSH).

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Authors and Affiliations

  1. Division of Hematological Malignancies, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA

    Evan M. Braunstein, Sergiu Pasca, Shiyu Wang & Lukasz P. Gondek

  2. Division of Hematology, Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA

    Evan M. Braunstein, Hang Chen & Alison Moliterno

  3. Division of Computational and Systems Pathology, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA

    Eddie Imada & Luigi Marchionni

  4. Committee on Genetics, Genomics and Systems Biology, Biological Sciences Division, University of Chicago, Chicago, IL, USA

    Hang Chen

  5. Henry Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA

    Camille Alba & Dan N. Hupalo

  6. The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Camille Alba & Clifton L. Dalgard

  7. Department of Anatomy Physiology & Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

    Matthew Wilkerson & Clifton L. Dalgard

  8. Laboratory of Myeloid Malignancies, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    Jack Ghannam & Christopher S. Hourigan

  9. Department of Biochemistry and Molecular Biology, Biological Sciences Division, University of Chicago, Chicago, IL, USA

    Yujia Liu

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  1. Evan M. Braunstein
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Contributions

AM, EMB and LPG identified and prepared biospecimens, and collected and annotated clinical data; CA, DH, MW, CLD, JG performed whole genome sequencing; EI and LM processed, analyzed, and interpreted WGS data; SP analyzed and interpreted clinical and sequencing data, performed genomic analysis, wrote and edited the manuscript; SW performed cell culture experiments and interpreted results; HC analyzed and interpreted sequencing data and performed protein modeling experiments; YL designed and performed protein modeling experiments; EMB and LPG supervised the experiments, interpreted the data, wrote and revised the manuscript; EMB, LPG, CH designed and funded the study. All authors critically reviewed the manuscript and approved the final version.

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Correspondence to Lukasz P. Gondek.

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Braunstein, E.M., Imada, E., Pasca, S. et al. Recurrent germline variant in ATM associated with familial myeloproliferative neoplasms. Leukemia 37, 627–635 (2023). https://doi.org/10.1038/s41375-022-01797-6

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