Impact of TP53 defects on venetoclax combinations. (A-D) Dynamic changes in clonal architecture from diagnosis to relapse in 4 illustrative cases with TP53 mutations. The VAF of each mutation is shown, along with the bone marrow blast count at the corresponding time point. The time elapsed from remission to treatment failure is shown in days. (E) Interval changes in chromosome 17 and TP53 at diagnosis and relapse. Patterns of clonal evolution of biallelic TP53 abnormalities in 5 AML cases at relapse. Changes in TP53 VAF % were quantitated by targeted NGS. Changes in chromosome 17 were assessed using standard karyotypic techniques. (F) Competitive growth assay comparing the survival of TP53 WT (gray) and TP53 CRISPR/Cas9–deleted (red) in MV4;11 cells during exposure to vehicle, venetoclax 100 nM, cytarabine (ara-C) 500 nM, decitabine 1 µM, venetoclax 100 nM plus low-dose cytarabine (LDAC) 100 nM, or venetoclax 100 nM plus decitabine (DEC) 1 µM in culture over a period of 10 days. The proportion of each cell genotype was indicated by a fluorescent reporter and enumerated by flow cytometry. The total cell viability (%) is shown above each bar. (G-I) Viability of RN2 cells (TP53 WT, p53^WT) or p53^R172H/Δ murine AML cell lines after exposure to venetoclax (G), venetoclax plus azacitidine (1 μM) (H), or venetoclax plus cytarabine (20 nM) (I) for 48 hours. The tables indicate the 50% inhibitory concentration values (nM). Errors represent the standard deviation of 3 technical replicates.