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

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.

A Murine Model of Chronic Lymphocytic Leukemia Based on B Cell-Restricted Expression of Sf3b1 Mutation and Atm Deletion

“…In striking contrast, however, DM-CLL cells were defective in initiating SYK and AKT phosphorylation upon stimulation (all p<0.05, Figure 6E-F). In addition, different from non-CLL cells, DM-CLL cells showed constitutive phosphorylation of ERK1/2 even without α-IgM stimuli (all p<0.01, Figure 6E-F), a phenotype previously described in self-reactive anergic B cells and subset of human CLLs (Blix et al, 2012; Duhren-von Minden et al, 2012; Herve et al, 2005; Marklin et al, 2017; Muzio et al, 2008; Yarkoni et al, 2010). Furthermore, we noted that DM-CLL cells had lower basal expression of AKT protein than the non-CLL mouse lines (Figure 6E-F, all p<0.05).…”

Loss of NFAT2 expression results in the acceleration of clonal evolution in chronic lymphocytic leukemia

“…We have recently demonstrated that deletion of NFAT2 in the context of the TCL1 transgenic mouse model leads to the loss of the anergic phenotype as well as to the development of disease transformation reminiscent of human Richter's syndrome . In this study, we could further demonstrate that NFAT2 expression was virtually absent in lymph node biopsies from human patients with Richter's syndrome whereas NFAT2 was overexpressed in primary tumor samples from patients with CLL.…”

“…Our group has recently demonstrated that NFAT2 deletion in TCL1 transgenic mice results in drastic acceleration of the observed CLL with significantly reduced overall survival (201 vs. 325 days) and eventual transformation to high grade lymphoma . We could also show that NFAT2 deletion results in an alteration of the signaling response induced upon BCR stimulation.…”

“…The family member NFAT2 has been demonstrated to be critical for the development of B1a cells . Furthermore, NFAT2 has been shown to be overexpressed and constitutively activated in indolent forms of human CLL . It is also involved in maintaining tumor cell survival and counteracting apoptosis in aggressive B cell lymphomas by regulating different survival factors such as BLyS and CD40L …”

“…We have recently demonstrated that NFAT2 is a critical regulator of anergy in CLL . Upon B cell‐specific deletion of NFAT2, TCL1 transgenic mice lose their anergic CLL phenotype and develop a significantly more aggressive disease that closely resembles human Richter's syndrome.…”