Abstract

Chronic lymphocytic leukaemia (CLL) is a clonal disorder of mature B cells. Most patients are characterised by an indolent disease course and an anergic phenotype of their leukaemia cells, which refers to a state of unresponsiveness to B cell receptor stimulation. Up to 10% of CLL patients transform from an indolent subtype to an aggressive form of B cell lymphoma over time (Richter´s syndrome) and show a significantly worse treatment outcome. Here we show that B cell-specific ablation of Nfat2 leads to the loss of the anergic phenotype culminating in a significantly compromised life expectancy and transformation to aggressive disease. We further define a gene expression signature of anergic CLL cells consisting of several NFAT2-dependent genes including Cbl-b, Grail, Egr2 and Lck. In summary, this study identifies NFAT2 as a crucial regulator of the anergic phenotype in CLL.

Details

Title
NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia
Author
Märklin, Melanie 1   VIAFID ORCID Logo  ; Heitmann, Jonas S 1 ; Fuchs, Alexander R 1 ; Truckenmüller, Felicia M 1 ; Gutknecht, Michael 1 ; Bugl, Stefanie 1 ; Saur, Sebastian J 1 ; Lazarus, Juliane 1 ; Kohlhofer, Ursula 2 ; Quintanilla-Martinez, Leticia 2   VIAFID ORCID Logo  ; Rammensee, Hans-Georg 3 ; Salih, Helmut R 4 ; Kopp, Hans-Georg 1 ; Haap, Michael 5 ; Kirschniak, Andreas 6 ; Kanz, Lothar 1 ; Rao, Anjana 7 ; Wirths, Stefan 1 ; Müller, Martin R 1 

1  Department of Oncology, Haematology and Immunology, University of Tübingen, Tübingen, Germany 
2  Department of Pathology, University of Tübingen, Tübingen, Germany 
3  Department of Immunology, University of Tübingen, Tübingen, Germany 
4  Department of Oncology, Haematology and Immunology, University of Tübingen, Tübingen, Germany; Clinical Collaboration Unit Translational Immunology, German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Heidelberg, Germany 
5  Department of Endocrinology, Diabetology, Clinical Pathology and Metabolism, University of Tübingen, Tübingen, Germany 
6  Department of Surgery, University of Tübingen, Tübingen, Germany 
7  La Jolla Institute of Allergy and Immunology, La Jolla, CA, USA 
Pages
1-14
Publication year
2017
Publication date
Oct 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-00830-y
ProQuest document ID
1945734065
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.