Deletion of IKZF1 leads to broadly increased chemoresistance. (A-D) and (G) Drug treatment of Nalm-6 clonal cell lines showing percent annexin V/7-AAD double-negative population as measured by flow cytometry. Samples were performed in triplicate; error bars show standard error of the mean, and statistical significance was calculated by using one-way analysis of variance. All assays were for 72 hours. Daunorubicin (A), asparaginase (B), methotrexate (no statistically significant difference) (C), and cytarabine (D). (E) Heatmap showing fold change of fragments per kilobase of transcript per million mapped reads (FPKM) of genes involved in cytarabine (Ara-C) enzymatic processing and membrane transport. Each data point shows the mean of 2 technical replicates. Fold changes are compared with WT sample mean. (F) western blot of SAMHD1 protein expression with lentivirally infected empty vector (EV) or ectopic SAMHD1 expressing constructs. Blot shown is a representative example from 3 experiments. (G) Cytarabine treatment with lentivirally transduced Nalm-6 cells. (H) SAMHD1 expression correlates with IKZF1 expression in B-ALL patient samples (PeCan database; n = 567 diagnostic RNAseq samples). (I) SAMHD1 locus from IKAROS chromatin immunoprecipitation sequencing (ChIPseq) from the ENCODE database, showing K562 and GM12878 (Epstein-Barr virus–transformed lymphoblastoid) cell lines.