靶向 Bcl-xL 是结外 NK/T 细胞淋巴瘤的一种潜在治疗策略

Extranodal natural killer/T cell lymphoma, nasal type (ENKTL) is an aggressive lymphoid malignancy with a poor prognosis and lacks standard treatment. Targeted therapies are urgently needed.

Here we systematically investigated the druggable mechanisms through chemogenomic screening and identified that Bcl-xL-specific BH3 mimetics effectively induced ENKTL cell apoptosis.

Notably, the specific accumulation of Bcl-xL, but not other Bcl-2 family members, was verified in ENKTL cell lines and patient tissues.

Furthermore, Bcl-xL high expression was shown to be closely associated with worse patient survival. The critical role of Bcl-xL in ENKTL cell survival was demonstrated utilizing selective inhibitors, genetic silencing, and a specific degrader.

Additionally, the IL2-JAK1/3-STAT5 signaling was implicated in Bcl-xL dysregulation. In vivo , Bcl-xL inhibition reduced tumor burden, increased apoptosis, and prolonged survival in ENKTL cell line xenograft and patient-derived xenograft models.

Our study indicates Bcl-xL as a promising therapeutic target for ENKTL, warranting monitoring in ongoing clinical trials by targeting Bcl-xL.