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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 up-regulated marker in MRD cells from PDXs and patients with diverse oncogenic subtypes. We further demonstrated that CD20 expression is induced by glucocorticoid exposure though the activation of the transcription factor SPIB, 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE309451 | GEO | 2026/09/23

REPOSITORIES: GEO

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Project description:Background: Mutant BRAF targeted therapies remain a standard of care for the treatment of metastatic malignant melanoma (MM); however high initial response rates are tempered by the persistence of residual MM cells that eventually lead to disease recurrence and mortality. Since MM recurrence during targeted therapy can present with the simultaneous occurrence of multiple tumour nodules at the original body sites, we hypothesised the presence of an intrinsically resistant MM cell sub-population. Objectives: Identify an MM cell subpopulation that is intrinsically resistant to targeted therapy and so may be responsible for MM recurrence. Methods: Using melanoma cell lines, we define culture conditions for reproducible 3D growth of melanospheres to investigate putative cancer stem cell populations. We undertook RNA sequencing and bioinformatic analysis to characterise cell populations between adherent and non-adherent culture, and cells expressing or not expressing CD20. Furthermore, we define an in vitro assay to evaluate killing of melanoma cancer stem cells as a therapeutic test using combination therapies targeting driver mutation and CD20 marker. Results: We have described culture conditions that promote MM cells to form melanospheres with a reproducible colony forming efficiency of 0.3% to 1.3%. RNA sequencing of melanosphere versus conventional MM cell cultures (n=6), irrespective of the BRAF mutation status, showed that melanosphere formation was associated with growth and differentiation transcriptional signatures resembling MM tumours. Importantly, melanosphere formation also led to the emergence of a CD20+ MM cell subpopulation, similar to that observed in primary human MM tumours. CD20+ MM cells were resistant to BRAF inhibitor therapy, and consistent with this finding demonstrated a Forkhead box protein M1 (FOXM1) transcriptomic profile (n=6). Combining BRAF inhibitor and anti-CD20 antibody treatment led to the additional killing of previously resistant CD20+ BRAF mutant MM cells. Conclusions: In MM patients that harbour a CD20+ sub-population, combined therapy with BRAF inhibitor and anti-CD20 antibody could potentially kill residual MM cells and so prevent disease recurrence.

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

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