GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE307nnn/GSE307727/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE307727GEOGSEfalseVenetoclax in the therapeutic strategy for BPDCN managementBackground: Venetoclax, a B-cell lymphoma 2 (BCL-2) inhibitor, is a promising treatment for blastic plasmacytoid dendritic cell neoplasm (BPDCN) and is currently under evaluation in clinical trials. However, several case reports have reported relapses after prolonged treatment, and development of resistance. To date, no study has investigated resistance to venetoclax in BPDCN. Therefore, we sought to investigate the mechanisms that trigger resistance during treatment. Methods: To this end, we developed an in vitro model of chronic exposure of a BPDCN cell line to venetoclax. We further characterized it and found an upregulation of BCL-xL, both at the genomic and proteomic level. Results: By combining venetoclax with a hypomethylating agent, we were able to overcome venetoclax resistance and induce resistant cell-line death. However, association with a proteasome inhibitor, known to be efficient against BPDCN, failed to restore sensitivity to venetoclax, probably due to modification of the NF-κB pathway observed by bulk-RNAseq analysis. Conclusions: Collectively, these data suggest that acquired venetoclax resistance in BPDCN is mediated by a modification of the balance of BCL-2 family proteins. Also, the mechanisms involved in resistance may also lead to resistance to other molecules among the drugs that might otherwise have been considered as alternative therapies.2026/09/01GSE307727GSM9229956GSM9229958GSM9229957GSM9229959GSM9229961GSM9229960GSM9229963GSM9229962GSM922996418573307727Homo sapiens