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

Abstract

Chronic lymphocytic leukemia (CLL) can be defined as a clonal expansion of B cells with stereotypic BCRs. Somatic hypermutation of the BCR heavy chains (IGVH) defines a subgroup of patients with a better prognosis. In up to 10% of CLL cases, a transformation to an aggressive B cell lymphoma (Richter's syndrome) with a dismal prognosis can be observed over time. NFAT proteins are transcription factors originally identified in T cells, which also play an important role in B cells. The TCL1 transgenic mouse is a well‐accepted model of CLL. Upon B cell‐specific deletion of NFAT2, TCL1 transgenic mice develop a disease resembling human Richter's syndrome. Whereas TCL1 B cells exhibit tonic anergic BCR signaling characteristic of human CLL, loss of NFAT2 expression leads to readily activated BCRs indicating different BCR usage with altered downstream signaling. Here, we analyzed BCR usage in wild‐type and TCL1 transgenic mice with and without NFAT2 deletion employing conventional molecular biology techniques and next‐generation sequencing (NGS). We demonstrate that the loss of NFAT2 in CLL precipitates the selection of unmutated BCRs and the preferential usage of certain VDJ recombinations, which subsequently results in the accelerated development of oligoclonal disease.

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

“…We further reported that these cells exhibit a constitutive activation of NFAT2 and ERK1/2 ( 16 ). We also recently demonstrated that loss of NFAT2 in the B cell compartment causes an aggressive course of CLL, enhances BCR signaling and results in the selection of unmutated BCRs and leads to a highly proliferative disease in a murine E μ -TCL1 leukemia model ( 16 , 20 ). This was mirrored by low NFAT2 expression in patients with Richter transformation ( 16 ).…”

“…Overall, the role of LCK in CLL is still not completely understood. Our previous finding that Lck is a direct target gene of NFAT2 in CLL and the essential role of LCK in acceleration and transformation of CLL ( 16 , 20 , 22 ) prompted us to investigate its precise function in disease pathophysiology. To this end, we employed a combination of the E μ -TCL1 transgenic mouse model and the LCK knockout model to further demonstrate that LCK deletion leads to acceleration and reversal of the anergic phenotype of CLL.…”

Role of NFAT in Chronic Lymphocytic Leukemia and Other B-Cell Malignancies

“…To better understand if NFAT deletion impacted directly on different BCR downstream signaling or rather on clonal selection of different BCR recombination, Muller et al. analyzed clonal evolution in leukemic mice and found that NFAT2 signaling in CLL cells precipitates the oligoclonal selection of preferentially unmutated BCRs ( 76 ).…”

Expression, Prognosis and Gene Regulation Network of NFAT Transcription Factors in Non-Small Cell Lung Cancer

“…In addition, Wang et al [ 37 ] reported that NFAT2 is overexpressed in HCC and promotes the proliferation of HepG2 cell lines, and Xu et al [ 7 ] indicated that NFAT2 is frequently inactivated in HCC and functions as a tumor suppressor gene to promote the apoptosis of HCC cells by activating the FasL-mediated extrinsic signaling pathway. Moreover, other studies have suggested the tumor suppressor role of NFAT2 in some types of cancer, including human lymphomas [ 38 ], chronic lymphocytic leukemia [ 39 ], colorectal cancer [ 40 ], and squamous skin cancer [ 41 ]. Regarding NSCLC, Zhang et al [ 42 ] reported that NFAT2 can function as a tumor suppressor gene to induce the apoptosis of A549 cells.…”