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Diffuse large B-cell lymphoma (DLBCL) represents the most common adult lymphoma that is divided into two major molecular subtypes, the germinal center B-cell-like (GCB) and the aggressive activated B-cell-like (ABC) DLBCL. Previous studies suggested that chronic BCR signaling and increased NF-κB activation contribute to ABC DLBCL. Here we show that the activity of the transcription factor NFAT is chronically elevated in both DLBCL subtypes. Surprisingly, NFAT activation was independent of BCR signaling, but mediated by an increased calcium flux and calcineurin-mediated dephosphorylation of NFAT. Intriguingly, although NFAT was activated in both DLBCL subtypes, long-term calcineurin inhibition by cyclosporin A or FK506, both clinically approved drugs, triggered potent cytotoxicity specifically in ABC DLBCL cells. The antitumor effects of calcineurin inhibitors were associated with the downregulation of c-Jun, IL-6 and IL-10, which were identified as NFAT target genes particularly important for survival of ABC DLBCL. Furthermore, calcineurin blockade synergized with BCL-2 and MCL-1 inhibitors in killing ABC DLBCL cells. Collectively, these findings identify constitutive NFAT signaling as a crucial functional driver of ABC DLBCL and highlight calcineurin inhibition as a novel strategy for the treatment of ABC DLBCL.
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This study investigated the role of NFAT/Fas/FasL axis in cardiomyocyte apoptosis following doxorubicin (DOX) treatment in rats, and evaluated the involvement and regulation of all NFAT members in car...
This study investigated if calcineurin/nuclear factor of activated T cells (NFAT) axis mediates the cardiac apoptosis in rats with type 1 diabetes mellitus (T1DM)-induced rats or administered chronica...
In neurons, regulation of activity-dependent transcription by the nuclear factor of activated T-cells (NFAT) depends upon Ca influx through voltage-gated L-type calcium channels (LTCC) and NFAT transl...
Stimulation of the Gαq-coupled receptors triggers the activation of gene transcription via the rise of intracellular Ca. To investigate the role of the Ca/calmodulin-dependent phosphatase calcineurin...
Emerging evidence demonstrates that epoxyeicosatrienoic acids (EETs) as important active eicosanoids that regulate cardiovascular homeostasis, but the mechanisms underlying its favorable anti-hypertro...
Aim of the study is measurement of NFAT-RGE (IL-2 (interleukin-2), IFN-γ (interferon-gamma), GM-CSF (granulocyte monocyte colony stimulating factor)) after tacrolimus (TAC) in de-novo imm...
This study will evaluate whether conversion from cyclosporine, a calcineurin inhibitor (CI) to sirolimus (SRL) results in improved long-term renal function without a negative impact on saf...
Current therapy to prevent organ rejection relies on the use of calcineurin inhibitors either cyclosporine or tacrolimus. Although these agents have been very successful in preventing ear...
The long-term use of calcineurin inhibitors (CNI) in patients who have received a kidney transplantation is associated with renal dysfunction and hypertension. The study will evaluate the ...
The 3C study will investigate whether reducing exposure to calcineurin inhibitors (by using more potent antibody induction treatment and/or an elective switch to sirolimus) can improve the...
A family of transcription factors characterized by the presence of highly conserved calcineurin- and DNA-binding domains. NFAT proteins are activated in the CYTOPLASM by the calcium-dependent phosphatase CALCINEURIN. They transduce calcium signals to the nucleus where they can interact with TRANSCRIPTION FACTOR AP-1 or NF-KAPPA B and initiate GENETIC TRANSCRIPTION of GENES involved in CELL DIFFERENTIATION and development. NFAT proteins stimulate T-CELL activation through the induction of IMMEDIATE-EARLY GENES such as INTERLEUKIN-2.
Compounds that inhibit or block the PHOSPHATASE activity of CALCINEURIN.
A CALCIUM and CALMODULIN-dependent serine/threonine protein phosphatase that is composed of the calcineurin A catalytic subunit and the calcineurin B regulatory subunit. Calcineurin has been shown to dephosphorylate a number of phosphoproteins including HISTONES; MYOSIN LIGHT CHAIN; and the regulatory subunits of CAMP-DEPENDENT PROTEIN KINASES. It is involved in the regulation of signal transduction and is the target of an important class of immunophilin-immunosuppressive drug complexes.
A disease of chronic diffuse irreversible airflow obstruction. Subcategories of COPD include CHRONIC BRONCHITIS and PULMONARY EMPHYSEMA.
Acute and chronic (see also BRAIN INJURIES, CHRONIC) injuries to the brain, including the cerebral hemispheres, CEREBELLUM, and BRAIN STEM. Clinical manifestations depend on the nature of injury. Diffuse trauma to the brain is frequently associated with DIFFUSE AXONAL INJURY or COMA, POST-TRAUMATIC. Localized injuries may be associated with NEUROBEHAVIORAL MANIFESTATIONS; HEMIPARESIS, or other focal neurologic deficits.