Dysregulation of TNFα-induced necroptotic signaling in chronic lymphocytic leukemia: suppression of CYLD gene by LEF1.

Impaired cell death program has been noted as one of the hallmarks of chronic lymphocytic leukemia (CLL) and contributes to its accumulation of malignant monoclonal B cells as well as to chemotherapy resistance. A cell can die through the apoptosis or necrosis pathway. Recent investigations suggest that in apoptotic-deficient conditions, such as most types of cancer, a process of programmed necrosis, called necroptosis, prevails. However, the detailed molecular mechanisms underlying this alternative cell death pathway are still not fully understood. Here we demonstrate that CLL cells failed to undergo necroptosis upon stimulation of TNFα combined with pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone (zVAD). Two core components of necroptotic machine, RIP3 and deubiquitinase cylindromatosis (CYLD), are markedly downregulated in CLL. Moreover, we identified lymphoid enhancer-binding factor 1 (LEF1), a downstream effector of the Wnt/β-catenin pathway, as a transcription repressor of CYLD in CLL. Knocking down LEF1 sensitizes CLL cells to TNFα/zVAD-induced necroptosis. The present investigation provides the first evidence that CLL cells have defects not only in apoptotic program but also in necroptotic signaling. Targeting the key regulators of necroptotic machine, such as LEF1, to restore this pathway may represent a novel approach for CLL treatment.