AUTHOR=Märklin Melanie , Fuchs Alexander R. , Tandler Claudia , Heitmann Jonas S. , Salih Helmut R. , Kauer Joseph , Quintanilla-Martinez Leticia , Wirths Stefan , Kopp Hans-Georg , Müller Martin R. 

TITLE=Genetic Loss of LCK Kinase Leads to Acceleration of Chronic Lymphocytic Leukemia

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.01995

DOI=10.3389/fimmu.2020.01995

ISSN=1664-3224

ABSTRACT=<p>Most patients with chronic lymphocytic leukemia (CLL) exhibit an indolent disease course and unresponsive B cell receptors (BCRs) exemplified by an anergic phenotype of their leukemic cells. In up to 5% of patients, CLL transforms from an indolent subtype to an aggressive form of B cell lymphoma (Richter's syndrome), which is associated with worse disease outcome and severe downregulation of NFAT2. Here we show that ablation of the tyrosine kinase LCK, which has previously been characterized as a main NFAT2 target gene in CLL, leads to loss of the anergic phenotype, thereby restoring BCR signaling, which results in an acceleration of CLL. Our study identifies LCK as a main player in mediating BCR unresponsiveness and its role as a crucial regulator of anergy in CLL.</p>