Fig. 3: Increased ESC replication in patients with BCP-ALL who later relapse.

a, Schematic highlighting that multiple copies of a recombination junction (white and pink) are present if recombination took place many cell divisions ago. b, SJs corresponding to very recent recombination events (≤0.2 normalized LAM-recombination reads) were identified. Normalized SJ reads were divided by corresponding normalized recombination reads. P value for the increase in patients who later relapsed determined by two-tailed Mann–Whitney U test; n = 74 SJs from 12 patients (relapse) and 51 SJs from 8 patients (non-relapse). c, Eleven SJs corresponding to ≤0.2 normalized recombination reads are in both patient groups. SJ levels were measured by ddPCR for patients who later relapsed (red) or remained in remission (blue). Data are mean observed/predicted SJ values, assuming a twofold SJ dilution at each cell division (Methods). Black dots indicate values for individual patients. P values determined using a two-tailed Wilcoxon signed-rank test. n = 11 pairs. SJ levels only shown for HeLa controls (orange dots; n = 2). d, Enrichment plot for DNA repair genes from GSEA of RNA-seq data from 123 patients at diagnosis, 74 of whom relapsed. Significance determined as described^53,54 with corrections for multiple comparisons. e, RT–qPCR analysis of expression of genes associated with DNA replication and repair in patients who later relapse (for patients with high (H-) or low (L-) SJ levels) or remain in remission (non-relapse). n = 11 for each group except L-relapse: n = 8 (PCNA) and 10 (POLE3); and non-relapse: n = 12 (RBX1). Data are normalized to HPRT expression. P values determined using an unpaired, two-tailed Student’s t-test. The 95% confidence interval is presented in Methods. Data are mean ± s.d. f, GSEA of RNA-seq data (EGAS00001006863) from patients with known SJ levels. Enrichment plot for DNA repair genes for patients with high versus low SJ levels (n = 4 and n = 3, respectively). P values determined as in d.

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