TNF receptor 2 is essential for RIP1-dependent cell death in refractory leukemia

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DOIResolve DOI: http://doi.org/10.1158/1538-7445.AM2017-4321
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TypeAbstract
Proceedings titleProceedings of the American Association for Cancer Research Annual Meeting 2017, 2017 Apr 1-5, Washington, DC
Series titleCancer Research; Volume 77
ConferenceAmerican Association for Cancer Research Annual Meeting 2017, April 1-5, 2017, Washington, DC, USA
ISSN0008-5472
1538-7445
Article numberAbstract nr 4321
AbstractThe identification of molecular determinants that regulate sensitivity to specific agents is essential for the development of new therapeutic approaches in cancer. We have earlier shown that a subset of refractory acute lymphoblastic leukaemia (ALL) samples respond to SMAC-mimetic (SM) induced IAP depletion by concurrently inducing RIP1-dependent apoptosis and necroptosis. Comparative gene expression profiling indicated a correlation of sensitivity to SM with the expression of TNF receptor 2 (TNFR2) in primary ALL. Using an independent cohort of primary chemotherapy-resistant ALL samples, we found that presence of high TNFR2 expression identified by qPCR predicted ex vivo-sensitivity to SM. High TNFR2 levels also correlated with higher expression of TNFR1. Deletion of either TNFR1 or TNFR2 using CRISPR/Cas9 in primary ALL conferred resistance to treatment with SM, indicating that TNFR1 and 2 are both functionally required for cell death. Concomitant with an important role for TNFR2 in the response to SM, the overexpression of TNFR2 leads to increased sensitivity to TNF through increased activation of the TNFR1/RIP1 death axis. On the mechanistic level, SM induced recruitment of RIP1 to TNFR1, which was abolished in cells deficient for TNFR2. Taken together, our data reveal a novel function of TNFR2 in cell death signalling, as TNFR2 predicts sensitivity to SMAC mimetics and plays a key role in modulating a switch from RIP1-controlled cell survival to cell death.
Publication date
PublisherAmerican Association for Cancer Research
LanguageEnglish
AffiliationHuman Health Therapeutics; National Research Council Canada
Peer reviewedYes
NPARC number23002150
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Record identifierb6b42a7f-48e0-4e99-b312-81e4a8c28802
Record created2017-08-25
Record modified2017-08-28
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