Tumour Necrosis Factor receptor (TNFR)-signalling dependent killing in T-cell acute lymphoblastic leukaemia (T-ALL)

Autocrine TNF can promote cell survival and leukaemia progression and is associated with poor prognosis. SMAC-mimetics (SM), pharmacological inhibitors of IAPs, are critical regulators of TNF-signalling and are able to sensitise leukaemias to TNF-induced cell death. Here, we examine the mechanism of SM-sensitivity by investigating individual components of the TNF-system.

We found constitutive low level expression of TNFR1, whereas cell surface TNFR2 was detected at various expression levels in approximately 30% of T-ALLs. As expected, SM birinapant-induced cell death was dependent on TNF production and promotes TNF-induced cell death in various T-ALL patient-derived xenografts (PDX). Interestingly, correlation analyses revealed a very good correlation between SM-sensitivity and cell surface TNFR2. In line with this, shRNA-mediated knockdown of TNFR2 is sufficient to significantly diminish TNF/SM-induced cell death in T-ALL cell lines, whereas ectopic expression of TNFR2 primed TNFR2-negative T-ALL cell lines for TNF/SM-induced cell death.

Together, our data demonstrate heterogeneous expression of TNFR2 in T-ALL, which determines the killing capacity of Smac-mimetic birinapant.