TY  - JOUR
A1  - Koch, Annkathrin
A1  - Jeiler, Birte
A1  - Rödig, Jens
A1  - Wijk, Sjoerd van
A1  - Dolgikh, Nadezda
A1  - Fulda, Simone
T1  - Smac mimetics and TRAIL cooperate to induce MLKL-dependent necroptosis in Burkitt’s lymphoma cell lines
T2  - Neoplasia
N2  - Burkitt's lymphoma (BL) is a highly aggressive form of B-cell non-Hodgkin's lymphoma. The clinical outcome in children with BL has improved over the last years but the prognosis for adults is still poor, highlighting the need for novel treatment strategies. Here, we report that the combinational treatment with the Smac mimetic BV6 and TRAIL triggers necroptosis in BL when caspases are blocked by zVAD.fmk (TBZ treatment). The sensitivity of BL cells to TBZ correlates with MLKL expression. We demonstrate that necroptotic signaling critically depends on MLKL, since siRNA-induced knockdown and CRISPR/Cas9-mediated knockout of MLKL profoundly protect BL cells from TBZ-induced necroptosis. Conversely, MLKL overexpression in cell lines expressing low levels of MLKL leads to necroptosis induction, which can be rescued by pharmacological inhibitors, highlighting the important role of MLKL for necroptosis execution. Importantly, the methylation status analysis of the MLKL promoter reveals a correlation between methylation and MLKL expression. Thus, MLKL is epigenetically regulated in BL and might serve as a prognostic marker for treatment success of necroptosis-based therapies. These findings have crucial implications for the development of new treatment options for BL.
KW  - Smac mimetics
KW  - TRAIL
KW  - Burkitt’s lymphoma
KW  - Necroptosis
KW  - MLKL
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/75556
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-755561
SN  - 1476-5586
VL  - 23
IS  - 5
SP  - 539
EP  - 550
PB  - Stockton Press
CY  - Basingstoke
ER  -