Targeting glucocorticoid-induced CD20 activation in preclinical models of B-ALL

Abstract

Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is effectively controlled with contemporary multi-agent chemotherapy, resulting to 5-year survival rates above 90%. However, relapse occurs in 15-20% of patients due to minimal residual disease (MRD), characterized by the presence of persisting and resistant leukemic cells, and associated with a poor clinical outcome. Despite its prognostic relevance, the molecular features driving MRD are poorly characterized. In this study, we developed patient-derived xenograft (PDX) models from matched diagnosis and relapse B-ALL samples combined to chemotherapy to mimic MRD in vivo. Drug-tolerant leukemic cells were profiled using single-cell RNA sequencing and we identified a transcriptionally distinct MRD-like population enriched for cell-quiescence, inflammatory stress, and B-cell receptor pathway signatures. Strikingly, the B-lymphocyte surface antigen CD20, encoding by MS4A1 gene, emerged as a consistent upregulated marker in MRD cells from PDXs and patients with diverse oncogenic subtypes. We further demonstrated that CD20 expression is induced by glucocorticoid exposure, creating a therapeutic opportunity where anti-CD20 monoclonal antibodies selectively eradicated MRD cells in vivo. Our data highlight CD20 not only as a biomarker but as an actionable vulnerability in B-ALL MRD, supporting clinical evaluation of anti-CD20 immunotherapy during induction treatment to kill drug-resistant cells and reduce relapse risk.