Jarmila Stremenova Spegarova
Germline TET2 loss of function causes childhood immunodeficiency and lymphoma
Stremenova Spegarova, Jarmila; Lawless, Dylan; Mohamad, Siti Mardhiana Binti; Engelhardt, Karin R.; Doody, Gina; Shrimpton, Jennifer; Rensing-Ehl, Anne; Ehl, Stephan; Rieux-Laucat, Frederic; Cargo, Catherine; Griffin, Helen; Mikulasova, Aneta; Acres, Meghan; Morgan, Neil V.; Poulter, James A.; Sheridan, Eamonn G.; Chetcuti, Philip; O'Riordan, Sean; Anwar, Rashida; Carter, Clive R.; Przyborski, Stefan; Windebank, Kevin; Cant, Andrew J.; Lako, Majlinda; Bacon, Chris M.; Savic, Sinisa; Hambleton, Sophie
Authors
Dylan Lawless
Siti Mardhiana Binti Mohamad
Karin R. Engelhardt
Gina Doody
Jennifer Shrimpton
Anne Rensing-Ehl
Stephan Ehl
Frederic Rieux-Laucat
Catherine Cargo
Helen Griffin
Aneta Mikulasova
Meghan Acres
Neil V. Morgan
James A. Poulter
Eamonn G. Sheridan
Philip Chetcuti
Sean O'Riordan
Rashida Anwar
Clive R. Carter
Professor Stefan Przyborski stefan.przyborski@durham.ac.uk
Dean of Infrastructure
Kevin Windebank
Andrew J. Cant
Majlinda Lako
Chris M. Bacon
Sinisa Savic
Sophie Hambleton
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.
Citation
Stremenova Spegarova, J., Lawless, D., Mohamad, S. M. B., Engelhardt, K. R., Doody, G., Shrimpton, J., …Hambleton, S. (2020). Germline TET2 loss of function causes childhood immunodeficiency and lymphoma. Blood, 136(9), 1055-1066. https://doi.org/10.1182/blood.2020005844
Journal Article Type | Article |
---|---|
Online Publication Date | Aug 27, 2020 |
Publication Date | 2020-08 |
Deposit Date | Sep 10, 2020 |
Journal | Blood |
Print ISSN | 0006-4971 |
Electronic ISSN | 1528-0020 |
Publisher | American Society of Hematology |
Peer Reviewed | Peer Reviewed |
Volume | 136 |
Issue | 9 |
Pages | 1055-1066 |
DOI | https://doi.org/10.1182/blood.2020005844 |
Public URL | https://durham-repository.worktribe.com/output/1292714 |
You might also like
Cell Senescence-Independent Changes of Human Skin Fibroblasts with Age
(2024)
Journal Article
Bioprinted autologous human skin equivalents for in vitro testing of therapeutic antibodies
(2024)
Journal Article
Downloadable Citations
About Durham Research Online (DRO)
Administrator e-mail: dro.admin@durham.ac.uk
This application uses the following open-source libraries:
SheetJS Community Edition
Apache License Version 2.0 (http://www.apache.org/licenses/)
PDF.js
Apache License Version 2.0 (http://www.apache.org/licenses/)
Font Awesome
SIL OFL 1.1 (http://scripts.sil.org/OFL)
MIT License (http://opensource.org/licenses/mit-license.html)
CC BY 3.0 ( http://creativecommons.org/licenses/by/3.0/)
Powered by Worktribe © 2024
Advanced Search