Venetoclax resistance in preclinical KMT2A-rearranged acute lymphoblastic leukemia models is characterized by high inter- and intra-model heterogeneity.

ABSTRACT: The BCL-2 inhibitor venetoclax (VEN) has emerged as an important therapeutic backbone for hematological malignancies, but secondary resistance is a major challenge. In acute lymphoblastic leukemia (ALL), early clinical trials promise high efficacy as well. However, relapse is observed frequently, and so far, only a few resistance-inducing mechanisms have been discussed. We employed KMT2A-rearranged ALL cell lines and xenograft models to elucidate mechanisms of VEN resistance. Targeted DNA and mRNA sequencing, single-cell mRNAseq, as well as protein expression analyses were conducted. All models initially responded well but finally displayed secondary resistance. Novel as well as previously known pathogenic variants in tumor suppressor TP53 as well as pro-apoptotic molecule BAX, but not BCL

SUBMITTER: Richter A 

PROVIDER: S-EPMC12855817 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature