KDM5-driven transcriptional noise fuels plasticity-led awakening and relapse in paediatric cancer
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How drug-tolerant persister (DTP) cells escape quiescence to drive tumour relapse is a central unresolved question in cancer evolution. Here, we identify transcriptional noise (TN), defined as the stochastic variability in gene expression, as a latent property of paediatric cancer cells that becomes a driver of adaptive regrowth after treatment withdrawal. Using functional assays, lineage tracing, single-cell transcriptomics, and multiscale landscape modelling, we show that therapy enriches mesenchymal-like tolerant states in neuroblastoma without clonal selection, while post-treatment awakening is a stochastic process fuelled by noise-enabled plasticity in cell-identity programmes. The histone demethylase KDM5A relocates to noisy cell-state genes during awakening, promoting H3K4me3 removal and chromatin remodelling at these loci. KDM5 inhibition abrogates this process, and suppresses transcriptional noise, halts DTP exit, and prevents tumour recovery in both neuroblastoma and hepatoblastoma models. These results establish DTP as an exploitable evolutionary bottleneck, positioning KDM5-mediated transcriptional noise as an actionable therapeutic target to limit cancer adaptation and relapse.
