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Venetoclax in the Therapeutic Strategy for BPDCN Management

Margaux Poussard1, Maxime Fredon1, Imane Belakri1

  • 1Université Marie et Louis Pasteur, EFS Bourgogne Franche-Comté, INSERM, UMR RIGHT Besançon France.

Ejhaem
|August 22, 2025
PubMed
Abstract

Insights

Venetoclax resistance in blastic plasmacytoid dendritic cell neoplasm (BPDCN) involves BCL-xL upregulation. Combining venetoclax with hypomethylating agents overcomes this resistance, unlike proteasome inhibitors.

Area of Science:

  • Oncology
  • Hematology
  • Molecular Biology

Background:

  • Venetoclax is a promising treatment for blastic plasmacytoid dendritic cell neoplasm (BPDCN).
  • Relapses and resistance to venetoclax have been reported, but mechanisms in BPDCN remain uninvestigated.
  • This study addresses the need to understand venetoclax resistance in BPDCN.

Purpose of the Study:

  • To investigate the mechanisms of acquired venetoclax resistance in BPDCN.
  • To develop and test strategies to overcome venetoclax resistance in BPDCN.

Main Methods:

  • Developed an in vitro model of chronic venetoclax exposure to induce resistance in a BPDCN cell line.
  • Characterized the resistant cell line using genomic and proteomic analyses.
  • Evaluated drug combinations to overcome venetoclax resistance.

Main Results:

  • Acquired resistance was associated with BCL-xL upregulation at genomic and protein levels.
  • Combination therapy with venetoclax and a hypomethylating agent overcame resistance and induced cell death.
  • Combination with a proteasome inhibitor failed to restore sensitivity, potentially due to NF-κB pathway modification.

Conclusions:

  • Venetoclax resistance in BPDCN is mediated by altered BCL-2 family protein balance.
  • Resistance mechanisms may confer cross-resistance to other therapies.
  • Hypomethylating agents represent a potential strategy to overcome venetoclax resistance in BPDCN.

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