Rouzier, C. | Search bioRxiv

bioRxiv2026

Novel regulators of zebrafish glomerular development

Podocyte cell differentiation in coordination with specialized endothelial cells forms the glomerulus, the kidney blood filter. Genetic analysis of animal models and human affected individuals has identified over 50 susceptibility genes that, when mutated, cause filtration defects or proteinuria. To explore the potential for new genetic pathways or components in glomerular development, we generated a transcriptome of micro-dissected three-day-post-fertilization zebrafish larval pronephric glomeruli and conducted a CRISPR-Cas9 G0 mutagenesis screen of less well characterized genes that showed glomerulus-enriched expression. Differential gene expression comparing glomeruli to whole larvae revealed a significant overlap of zebrafish glomerular-enriched gene expression with the human podocyte transcriptome. CRISPR-Cas9 G0 mutagenesis of twelve genes identified eight potential new causes of proteinuria in larval zebrafish based on glomerular leakage of rhodamine-labelled, 500 kDa high molecular weight dextran. Novel causes of proteinuria include regulators of small GTPases (fam49ba/cyrib, rasgrp3), cell adhesion/phosphatidylinositol metabolism (ptprq), and an upstream regulator of the hippo pathway (frmd6). Our glomerular transcriptome and screening results open new opportunities to explore glomerular cell differentiation and function.

developmental biology↗

bioRxiv2025

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

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.

cancer biology↗