Schematics of novel recurrent mutations in CTCL. (A) Distribution of mutations of VAV1, SMARCB1, and PTPRN2 in CTCL and ATLL. If the amino acid alterations occur at the same position, each amino acid substitution is separated by a vertical line. (B) Distribution of mutations in RARA in CTCL and ATLL. (C) Protein structure of RARA (PDB ID: 1DKF),⁴⁸  showing the locations of some CTCL mutations. The mutations cluster adjacent to the ligand binding pocket. (D) Distribution of mutations in CSNK1A1 in CTCL and ATLL. (E) Protein structure of CK1α (PDB ID: 5FQD), which is encoded by CSNK1A1.⁴⁹  The location of residue Ser27 is indicated at the tip of the glycine rich P-loop. (F) The CK1α mutations increased CD28-dependent TCR activation. Jurkat cells were transduced with CK1α WT or mutations either of p.S27C or p.S27F. These cells were treated with vehicle control or PMA (50 ng/mL)/ionomycin (300 ng/mL) and CD86 at the indicated concentrations. Data represent as mean ± standard error from 6 independent experiments. P value was determined by 2-sided paired ratio t test. **P < .01 For panels A, B, and D: C1, phorbol esters/diacylglycerol binding domain; CC, coiled-coil domain; CH, indicates calponin homology domain; DBD, DNA binding domain; Kinase, protein kinase domain; LBD, ligand binding domain; PH, pleckstrin homology; Repeat, repeat motif; RhoGEF, RhoGEF domain; SH2, SH2 domain; SH3, SH3 domain; Y-phosphatase, protein-tyrosine phosphatase.