Long isoform–specific disruption of CIC. (A) Isoform-specific protein and gene structures of CIC. mRNA and protein reference sequences are shown in supplemental Table 23. (B) Type and position of SVs and mutations within CIC region detected by WGS for 150 ATL cases, together with CIC mutations in other cancer types in the PCAWG project. (C) Frequency of CIC mutations in ATL and other cancer types from the PCAWG project¹ (with CIC mutation frequency ≥10%) according to mutation type (with or without truncating mutations) and location (CIC-L–specific vs –shared). Number of cases in each cohort is shown in parenthesis. Truncating mutations include stopgain single nucleotide variants (SNVs), frameshift indels, and canonical splice-site (SS) mutations. (D) RNA-seq read coverages of CIC region from CIC wild-type (WT) and -altered ATL cases and healthy CD4⁺ T cells. (E) Single-sample gene set enrichment analysis (ssGSEA) scores in CIC WT (n = 45) and -altered (n = 21) ATL cases, using gene signatures upregulated in activated (left) or naive (right) CD4⁺ T cells from Cic KO mice.²¹ Box plots show medians (lines), interquartile ranges (IQRs; boxes), and ± 1.5 × IQR (whiskers). Numbers of cases are shown in parentheses. Two-sided Brunner-Munzel test. (F) Pairwise associations among 15 driver alterations found in ≥20% of cases. Significant correlations (q < 0.1) colored according to their odds ratios are shown. Two-sided Fisher's exact test with Benjamini-Hochberg correction. (G) Schematic representation of Cic-L and Cic-S cKO mouse experiments. (H) Number of CD4⁺CD25⁺CD127^-Foxp3⁺ cells per spleen from CD4⁺ T-cell–specific homozygous Cic-L and Cic-S cKO mice (n = 4-5). Data represent means + standard deviation. Two-sided Welch's t test. BD, binding domain; COAD-US, colon adenocarcinoma from the US; HMG, high mobility group box; LGG-US, brain lower grade glioma from the United States (US); NLS, nuclear localization signal; STAD-US, gastric adenocarcinoma from the US.