Hubmann, Rainer and Schnabl, Susanne and Araghi, Mohammad and Schmidl, Christian and Rendeiro, Andre F. and Hilgarth, Martin and Demirtas, Dita and Ali, Farghaly and Staber, Philipp B. and Valent, Peter and Zielinski, Christoph and Jaeger, Ulrich and Shehata, Medhat (2020) Targeting Nuclear NOTCH2 by Gliotoxin Recovers a Tumor-Suppressor NOTCH3 Activity in CLL. CELLS, 9 (6): 1484. ISSN , 2073-4409
Full text not available from this repository. (Request a copy)Abstract
NOTCH signaling represents a promising therapeutic target in chronic lymphocytic leukemia (CLL). We compared the anti-neoplastic effects of the nuclear NOTCH2 inhibitor gliotoxin and the pan-NOTCH gamma-secretase inhibitor RO4929097 in primary CLL cells with special emphasis on the individual roles of the different NOTCH receptors. Gliotoxin rapidly induced apoptosis in all CLL cases tested, whereas RO4929097 exerted a variable and delayed effect on CLL cell viability. Gliotoxin-induced apoptosis was associated with inhibition of theNOTCH2/FCER2(CD23) axis together with concomitant upregulation of theNOTCH3/NR4A1axis. In contrast, RO4929097 downregulated theNOTCH3/NR4A1axis and counteracted the spontaneous and gliotoxin-induced apoptosis. On the cell surface, NOTCH3 and CD23 expression were mutually exclusive, suggesting that downregulation of NOTCH2 signaling is a prerequisite for NOTCH3 expression in CLL cells. ATAC-seq confirmed that gliotoxin targeted the canonical NOTCH signaling, as indicated by the loss of chromatin accessibility at the potential NOTCH/CSL site containing the gene regulatory elements. This was accompanied by a gain in accessibility at the NR4A1, NF kappa B, and ATF3 motifs close to the genes involved in B-cell activation, differentiation, and apoptosis. In summary, these data show that gliotoxin recovers a non-canonical tumor-suppressing NOTCH3 activity, indicating that nuclear NOTCH2 inhibitors might be beneficial compared to pan-NOTCH inhibitors in the treatment of CLL.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | LYMPHOCYTIC-LEUKEMIA CLL; KINASE-C-DELTA; B-CLL; APOPTOSIS; EXPRESSION; INHIBITOR; CANCER; CELLS; TRANSCRIPTION; ACTIVATION; chronic lymphocytic leukemia (CLL); NOTCH2; NOTCH3; FCER2 (CD23); NR4A1; gliotoxin; RO4929097; gamma-secretase inhibitors; ATAC-seq; binary cell fate decision; positive/negative selection; CD5+B-cell homeostasis |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Zentren des Universitätsklinikums Regensburg > Regensburger Centrum für Interventionelle Immunologie (RCI) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 24 Mar 2021 09:59 |
| Last Modified: | 24 Mar 2021 09:59 |
| URI: | https://pred.uni-regensburg.de/id/eprint/44452 |
Actions (login required)
 |
View Item |
