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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

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • 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