Germline TET2 loss of function causes childhood immunodeficiency and lymphoma

Blood. 2020 Aug 27;136(9):1055-1066. doi: 10.1182/blood.2020005844.

Jarmila Stremenova Spegarova ¹, Dylan Lawless ², Siti Mardhiana Binti Mohamad ³, Karin R Engelhardt ¹, Gina Doody ², Jennifer Shrimpton ², Anne Rensing-Ehl ⁴, Stephan Ehl ⁴, Frederic Rieux-Laucat ⁵, Catherine Cargo ⁶, Helen Griffin ¹, Aneta Mikulasova ⁷, Meghan Acres ¹, Neil V Morgan ⁸, James A Poulter ², Eamonn G Sheridan ², Philip Chetcuti ⁹, Sean O'Riordan ⁹, Rashida Anwar ², Clive R Carter ¹⁰, Stefan Przyborski ¹¹, Kevin Windebank ¹², Andrew J Cant ¹ ¹³, Majlinda Lako ⁷, Chris M Bacon ¹² ¹⁴, Sinisa Savic ¹⁰ ¹⁵, Sophie Hambleton ¹ ¹³

Affiliations

1 Primary Immunodeficiency Group, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom.
2 Leeds Institute of Medical Research, St. James's University Hospital, University of Leeds, Leeds, United Kingdom.
3 Regenerative Medicine Cluster, Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Penang, Malaysia.
4 Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Freiburg, Germany.
5 Université de Paris, Institut Imagine, Paris, France.
6 Haematological Malignancy Diagnostic Service, St James's University Hospital, Leeds, United Kingdom.
7 Newcastle University Biosciences Institute, Newcastle upon Tyne, United Kingdom.
8 Institute of Cardiovascular Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom.
9 Department of Paediatrics, Leeds General Infirmary, Leeds, United Kingdom.
10 Department of Clinical Immunology and Allergy, St James's University Hospital, Leeds, United Kingdom.
11 Department of Biosciences, Durham University, Durham, United Kingdom.
12 Wolfson Childhood Cancer Research Centre, Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, United Kingdom.
13 Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom.
14 Department of Cellular Pathology, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom; and.
15 NIHR, Leeds Biomedical Research Centre and Leeds Institute of Rheumatic and Musculoskeletal Medicine, Wellcome Trust Brenner Building, St James's University Hospital, Leeds, United Kingdom.

PMID: 32518946 DOI: 10.1182/blood.2020005844

Abstract

Molecular dissection of inborn errors of immunity can help to elucidate the nonredundant functions of individual genes. We studied 3 children with an immune dysregulation syndrome of susceptibility to Infection, lymphadenopathy, hepatosplenomegaly, developmental delay, autoimmunity, and lymphoma of B-cell (n = 2) or T-cell (n = 1) origin. All 3 showed early autologous T-cell reconstitution following allogeneic hematopoietic stem cell transplantation. By whole-exome Sequencing, we identified rare homozygous germline missense or nonsense variants in a known epigenetic regulator of gene expression: ten-eleven translocation methylcytosine dioxygenase 2 (TET2). Mutated TET2 protein was absent or enzymatically defective for 5-hydroxymethylating activity, resulting in whole-blood DNA hypermethylation. Circulating T cells showed an abnormal immunophenotype including expanded double-negative, but depleted follicular helper, T-cell compartments and impaired Fas-dependent Apoptosis in 2 of 3 patients. Moreover, TET2-deficient B cells showed defective class-switch recombination. The hematopoietic potential of patient-derived induced pluripotent stem cells was skewed toward the myeloid lineage. These are the first reported cases of autosomal-recessive germline TET2 deficiency in humans, causing clinically significant immunodeficiency and an autoimmune lymphoproliferative syndrome with marked predisposition to lymphoma. This disease phenotype demonstrates the broad role of TET2 within the human immune system.

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