Sox4 promotes leukemic transformation in vivo and is correlated with poor clinical outcome. Sox4^fl/fl ALL cells were transduced with 4-OHT–inducible Cre or an empty vector control (EV) and labeled with firefly luciferase. One × 10⁶ cells were injected into sublethally irradiated (2.5 Gy) NOD/SCID mice and leukemic expansion was tracked by luciferase bioimaging (A). In panel B overall survival of transplant recipient mice is shown in a Kaplan-Meier analysis (7 mice per group; P = .0007). The methylation status of the SOX4 promoter was studied (HELP assay²⁰ ; C) in normal human bone marrow pre-B cells (n = 12) and bone marrow biopsies of human Ph⁺ ALL (n = 83; P = 1.5 ×10⁻⁶; data from ECOG E2993 and ECOG leukemia tissue bank). In panel D, samples from patients with high risk ALL (n = 31) are compared with patients with intermediate risk ALL in relation to their SOX4 mRNA levels (n = 23, P = .07; ALL REZ BFM 2002,¹²  GSE4698). In panel E, we analyzed clinical and gene expression data from the pediatric ALL trial COG P9906¹⁴  (GSE36543). Samples from 207 patients were divided into 2 groups according to higher (red curve; n = 103) or lower (green; n = 104) than mean expression of Sox4 among all patients. The Kaplan-Meier analysis of overall survival shows a significant difference between the 2 groups (P = .046; H).