Figure 1.

Example showing the multistep acquisition of resistance in ALL. Cells are represented with mutations shown as small colored circles. At diagnosis (D), patient SJALL043859 had a subclonal mutation in SNRNP25 of uncertain significance in 10% of leukemic cells (10% cancer cell fraction or CCF), which increased to 87% at relapse (R). At relapse, an NT5C2 R367Q mutation was detected at 84% CCF within the SNRNP25 lineage, but was not found at diagnosis at 747× coverage, indicating that the NT5C2 variant descended from the SNRNP25 clone. The relapse sample also acquired the thiopurine signature (bottom), and the NT5C2 mutations had >50% probability of having been induced by thiopurines because it occurred at a thiopurine-preferred trinucleotide context. These findings are based on whole-genome sequencing and targeted deep sequencing (484 to 1284× coverage of the SNRNP25 and NT5C2 mutations).