Charting the genomic evolution of de novo AML at diagnosis, remission, and REL. (A) Frequently mutated genes and karyotype aberrations at time of diagnosis in the Penn AML cohort (total n = 182 patients). Patients are annotated by the treatments received throughout the course of the disease and by ELN 2022 risk classifications. (B) Distribution of the number of serial genomic profiles obtained for each patient, expressed as a percentage of the total cohort. All patients included in the cohort underwent genomic profiling at least twice, with more than half having ≥3 matched genomic samples. The number of patients in each category is annotated above. (C) Distribution of the number of patients with a genomic profile at each stage of AML disease progression, expressed as a percentage of the total cohort. The number of patients represented in each category is annotated above. (D-G) Comparison of cohort-level mutation (mut) frequencies across different disease time points; (D) diagnosis (n = 182) vs CR1 (n = 119); (E) CR1 vs REL1 (n = 76); (F) diagnosis vs REL1; and (G) REF1 (n = 27) vs REL1. Mut frequencies are calculated from all samples at each time point, irrespective of patient-level sample matching. Point sizes are scaled by statistical significance (Fisher's 2-sided exact test) and colored based on mut frequency. Asterisks indicate P < .05. Dashed lines denote equality between disease stages. ATO, arsenic trioxide; ATRA, all-trans retinoic acid; chr, chromosome; ELN, European LeukemiaNet; HDACi, histone deacetylase inhibitor; HMA, hypomethylating agent; IDHi, IDH inhibitor; MEC, mitoxantrone etoposide and cytarabine.