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

Ilenia Sana,Piera Angelillo,Maria Elena Mantione,Marta Muzio

doi:10.3389/fonc.2021.651057

Abstract

In recent years significant progress has been made in the clinical management of chronic lymphocytic leukemia (CLL) as well as other B-cell malignancies; targeting proximal B-cell receptor signaling molecules such as Bruton Tyrosine Kinase (BTK) and Phosphoinositide 3-kinase (PI3Kδ) has emerged as a successful treatment strategy. Unfortunately, a proportion of patients are still not cured with available therapeutic options, thus efforts devoted to studying and identifying new potential druggable targets are warranted. B-cell receptor stimulation triggers a complex cascade of signaling events that eventually drives the activation of downstream transcription factors including Nuclear Factor of Activated T cells (NFAT). In this review, we summarize the literature on the expression and function of NFAT family members in CLL where NFAT is not only overexpressed but also constitutively activated; NFAT controls B-cell anergy and targeting this molecule using specific inhibitors impacts on CLL cell viability. Next, we extend our analysis on other mature B-cell lymphomas where a distinct pattern of expression and activation of NFAT is reported. We discuss the therapeutic potential of strategies aimed at targeting NFAT in B-cell malignancies not overlooking the fact that NFAT may play additional roles regulating the inflammatory microenvironment.

Highlights

Targeting B-Cell Receptor Signaling in Chronic Lymphocytic LeukemiaIn recent years there have been significant improvements in the field of chronic lymphocytic leukemia (CLL) from both bench and bedside perspectives
Several lines of research led to the development of small molecule inhibitors of the kinases that transmit the signals from the proximal B-cell receptor (BCR) signaling complex to the downstream Transcription Factors (TFs) [i.e. Bruton Tyrosine Kinase (BTK) and Phosphoinositide 3-kinases delta (PI3Kd)] [2, 3]
We explored the biology of a key family of transcription factors that are activated after BCR stimulation, namely Nuclear Factor of Activated T cells (NFAT)

Summary

INTRODUCTION

In recent years there have been significant improvements in the field of chronic lymphocytic leukemia (CLL) from both bench and bedside perspectives. CLL cells are addicted to different microenvironmental stimuli with a key role being played by the B-cell receptor (BCR) stimulation and/or constitutive cell autonomous BCR activation [1] leading to cell survival and proliferation On this scientific basis, several lines of research led to the development of small molecule inhibitors of the kinases that transmit the signals from the proximal BCR signaling complex to the downstream Transcription Factors (TFs) [i.e. Bruton Tyrosine Kinase (BTK) and Phosphoinositide 3-kinases delta (PI3Kd)] [2, 3]. Novel therapeutic strategies are needed to cure refractory patients and to perhaps achieve deeper response with the intent of fully eradicating the disease In this context, we hypothesize that exploring other downstream signaling mediators including transcription factors may reveal novel vulnerabilities of malignant B cells, which could be of aid in treating CLL and other B cell malignancies. Chromosome n° of splice variants (Uniprot) n° of splice variants (Ensembl) total n° of isoforms n° of different protein coding variants

NCBI RNA expression in RNA expression in blood*

NFAT EXPRESSION AND ACTIVATION IN CLL AND OTHER LYMPHOID MALIGNANCIES

Expression Pattern and Functional Role of NFAT in CLL

Therapeutic Perspectives

DISCUSSION