Fig. 3: Mutational signatures and clonal evolution patterns.

a Mutational signatures at relapse in ALL (left) and AML (right). Each patient is annotated based on age, KMT2A-r, treatment, survival, and relapse group. Each signature is classified into Chemotherapy treatment (mutations due to thiopurine exposure (SBS87) is highlighted), Mismatch repair (MMR), APOBEC/AID, UV, Clock-like, Miscellaneous (Chemical exposure/Tobacco/ROS/Bacterial) or Unknown. The most prominent known signature is denoted under the bar chart, with an asterisk if the most common signature was ‘unknown’. Mutations in significantly mutated pathways are colored based on whether the mutation was found at diagnosis (yellow), relapse (lilac), or both (gray). Note, for P89, the third relapse was analyzed. b 2D plots showing the assignment of mutations to clusters at diagnosis and relapse, with each showing a representative patient with multiple clones seeding relapse, or with a clonal sweep that either was or was not detected at diagnosis, and at the bottom, the fraction of patients is stated. VAF=variant allele frequency. c The fraction of patients with multiple clones seeding relapse, or with a clonal sweep that was or was not detected at diagnosis, separated by leukemia type and when the patient relapsed. d Heatmap showing mutated genes in the indicated pathways in patients with multiple relapses. Annotated on top: KMT2A-r, sequencing type, and number of mutations. The number of mutations is only counted for samples that underwent WGS; Note for P30, WGS was performed on a sample 21 days (estimated around 15% leukemia cells) from diagnosis in addition to the relapse samples. SNP-array data is included for the diagnostic sample. e Clonal evolution depicted for P89 with multiple relapses, illustrated by a fish plot. At the top, the different treatment blocks are indicated, and at the bottom, the sampling day from diagnosis by tick marks. A circle above the tick mark shows if the sample was from BM (grey) or PB (red), CR complete remission, R1 first relapse, R2 second relapse, R3 third relapse. Samples sequenced by targeted sequencing, WGS, and WES are shown in bold. Non-silent mutations and their clonal relationship are indicated.