Expression of ENL YEATS domain tumor mutations in nephrogenic or stromal lineage impairs kidney development.

ABSTRACT: Recurrent gain-of-function mutations in the histone reader protein ENL have been identified in Wilms tumor, the most prevalent pediatric kidney cancer. However, their pathological significance in kidney development and tumorigenesis in vivo remains elusive. Here, we generate mouse models mimicking ENL tumor (ENL^T) mutations and show that heterozygous mutant expression in Six2⁺ nephrogenic or Foxd1⁺ stromal lineages leads to severe, lineage-specific kidney defects, both resulting in neonatal lethality. Six2-ENL^T mutant kidneys display compromised cap mesenchyme, scant nephron tubules, and cystic glomeruli, indicative of premature progenitor commitment and blocked differentiation. Bulk and spatial transcriptomic analyses reveal aberrant activation

SUBMITTER: Xue Z 

PROVIDER: S-EPMC11909213 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature