Extended Data Fig. 11: Model outlining the impact of increased ESC levels on BCP-ALL progression.

In patients prone to relapse (left), increased RAG1 expression will lead to increased secondary recombination and the generation of new ESCs. This, combined with cell-intrinsic factors that cause increased ESC replication, results in higher ESC levels. These ESCs can combine with RAG proteins to trigger DSBs at cRSSs in the genome via the cut-and-run reaction. Ongoing mutations, including those at frequently mutated and relapse-associated genes, lead to an increased mutational burden that is inherited by all daughter cells, promoting treatment resistance and relapse. In patients who are unlikely to relapse (right), although new ESCs are generated, the absence of significant ESC replication results in a lower mutational burden and a decreased likelihood of treatment resistance.