Targeting chronic NFAT activation with calcineurin inhibitors in diffuse large B-cell lymphoma
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00216208%3A11110%2F20%3A10411150" target="_blank" >RIV/00216208:11110/20:10411150 - isvavai.cz</a>
Alternative codes found
RIV/00064165:_____/20:10411150
Result on the web
<a href="https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=G2GsZieiZj" target="_blank" >https://verso.is.cuni.cz/pub/verso.fpl?fname=obd_publikace_handle&handle=G2GsZieiZj</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1182/blood.2019001866" target="_blank" >10.1182/blood.2019001866</a>
Alternative languages
Result language
angličtina
Original language name
Targeting chronic NFAT activation with calcineurin inhibitors in diffuse large B-cell lymphoma
Original language description
Diffuse large B-cell lymphoma (DLBCL) represents the most common adult lymphoma and can be divided into 2 major molecular subtypes: the germinal center B-cell-like and the aggressive activated B-cell-like (ABC) DLBCL. Previous studies suggested that chronic B-ceN receptor signaling and increased NF-kappa B activation contribute to ABC DLBCL survival. Here we show that the activity of the transcription factor NFAT is chronically elevated in both DLBCL subtypes. Surprisingly, NFAT activation is independent of B cell receptor signaling, but mediated by an increased calcium flux and calcineurin-mediated dephosphorylation of NFAT. Intriguingly, although NFAT is activated in both DLBCL subtypes, long-term calcineurin inhibition with cydosporin A or FK506, both clinically approved drugs, triggers potent cytotoxicity specifically in ABC DLBCL cells. The antitumor effects of calcineurin inhibitors are associated with the reduced expression of c-Jun, interleukin-6, and interleukin-10, which were identified as NFAT target genes that are particularly important for the 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 this aggressive lymphoma subtype.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30205 - Hematology
Result continuities
Project
<a href="/en/project/NV19-08-00144" target="_blank" >NV19-08-00144: Humanized patient-derived murine xenografts for experimental therapy of hematologic malignancies and for the study of in vivo acquired drug-resistance</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Blood
ISSN
0006-4971
e-ISSN
—
Volume of the periodical
135
Issue of the periodical within the volume
2
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
121-132
UT code for WoS article
000506638500006
EID of the result in the Scopus database
2-s2.0-85077761620