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Cytogenetics and molecular genetics

Familial myeloid malignancies with germline TET2 mutation

Leukemia volume 34, pages 1450–1453 (2020)Cite this article

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Since their first description about 10 years ago, TET2 mutations have been extensively studied and have greatly improved our knowledge about hematological malignancies and their epigenetic component [1]. The TET2 gene, located at 4q24, encodes an evolutionarily conserved methylcytosine dioxygenase that catalyzes the conversion of 5-methylcytosine to 5-hydroxymethylcytosine to promote DNA demethylation and modulate gene expression [2]. The TET2 protein plays important roles in hematopoiesis, including hematopoietic stem cell (HSC) self-renewal, lineage commitment, and terminal differentiation of monocytes [2]. Analysis of Tet2-knockout mice, which are viable, fertile and develop grossly normally, demonstrated that TET2 functions as a tumor suppressor whose haploinsufficiency increases susceptibility to hematological diseases [2]. TET2 has been shown to be one of the most mutated genes in human myeloid malignancies. TET2 mutations are found in about 40–50% of chronic myelomonocytic leukemia (CMML) [3], 20–25% of myelodysplastic syndrome [4] and de novo acute myeloid leukemia (AML) [5] and 10–15% of BCR-ABL1-negative myeloproliferative neoplasms (MPN) [6]. In addition, TET2 mutations are a common feature of age-related clonal hematopoiesis (CH) [7] and their incidence in myeloid malignancies have been shown to increase with age [8]. Although the TET2 gene has been widely sequenced in large cohorts of patients, evidence of inherited TET2 mutations have only been reported recently [9, 10]. Kaasinen et al. described a Finnish family with multiple cases of lymphoma segregating with a heterozygous germline TET2 frameshift variant.

Here, we describe a French pedigree harboring another germline TET2 frameshift variant in which three sibling developed myeloid malignancies.

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Fig. 1: Germline TET2 mutation with myeloid malignancies.

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Acknowledgements

We thank the family members who participated in this study. We thank Christophe Roumier (Tumor Bank, certification NF 96900-2014/65453-1, Centre Hospitalier Universitaire de Lille) for handling, conditioning, and storing patient samples.

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Authors and Affiliations

  1. CHU Lille, Laboratory of Hematology, F-59000, Lille, France

    Nicolas Duployez, Laurène Fenwarth, Alice Marceau-Renaut, Thomas Boyer, Elise Fournier, Olivier Nibourel & Claude Preudhomme

  2. INSERM, UMR-S 1172, F-59000, Lille, France

    Nicolas Duployez, Laurène Fenwarth, Alice Marceau-Renaut, Thomas Boyer, Olivier Nibourel, Catherine Roche-Lestienne, Guillemette Huet, Céline Berthon, Bruno Quesnel & Claude Preudhomme

  3. CHU Lille, Department of Hematology, F-59000, Lille, France

    Laure Goursaud, David Beauvais, Céline Berthon, Nathalie Cambier & Bruno Quesnel

  4. CH Lens, Department of Hematology, F-62307, Lens, France

    Claire Bories

  5. CH Dunkerque, Laboratory of Hematology, F-59385, Dunkerque, France

    Elise Fournier

  6. CHU Lille, Department of Medical Genetics, F-59000, Lille, France

    Catherine Roche-Lestienne

  7. CHU Lille, Cell Culture Department, F-59000, Lille, France

    Guillemette Huet

  8. CH Valenciennes, Department of Hematology, F-59322, Valenciennes, France

    Nathalie Cambier

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  1. Nicolas Duployez
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Contributions

ND, LF, AMR, and ON performed molecular studies and analyzed mutational data. TB and EF performed morphological examinations and flow cytometry. CRL performed genetic analysis. GH performed fibroblast culture. LG, CB, DB, CB, NC, and BQ provided samples and clinical data. ND and CP wrote the manuscript, which was approved by all the authors.

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Correspondence to Nicolas Duployez.

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Duployez, N., Goursaud, L., Fenwarth, L. et al. Familial myeloid malignancies with germline TET2 mutation. Leukemia 34, 1450–1453 (2020). https://doi.org/10.1038/s41375-019-0675-6

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