NFAT2 is a critical regulator of the anergic phenotype in chronic lymphocytic leukaemia

Melanie Märklin, Jonas S. Heitmann, Alexander R. Fuchs, Felicia M. Truckenmüller, Michael Gutknecht, Stefanie Bugl, Sebastian J. Saur, Juliane Lazarus, Ursula Kohlhofer, Leticia Quintanilla-Martinez, Hans-Georg Rammensee, Helmut R. Salih, Hans-Georg Kopp, Michael Haap, Andreas Kirschniak, Lothar Kanz, Anjana Rao, Stefan Wirths and Martin R. Müller ()
Additional contact information
Melanie Märklin: University of Tübingen
Jonas S. Heitmann: University of Tübingen
Alexander R. Fuchs: University of Tübingen
Felicia M. Truckenmüller: University of Tübingen
Michael Gutknecht: University of Tübingen
Stefanie Bugl: University of Tübingen
Sebastian J. Saur: University of Tübingen
Juliane Lazarus: University of Tübingen
Ursula Kohlhofer: University of Tübingen
Leticia Quintanilla-Martinez: University of Tübingen
Hans-Georg Rammensee: University of Tübingen
Helmut R. Salih: University of Tübingen
Hans-Georg Kopp: University of Tübingen
Michael Haap: University of Tübingen
Andreas Kirschniak: University of Tübingen
Lothar Kanz: University of Tübingen
Anjana Rao: La Jolla Institute of Allergy and Immunology
Stefan Wirths: University of Tübingen
Martin R. Müller: University of Tübingen

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00830-y

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