An integrated analysis was performed on 354 adolescent and young adult (AYA) and adult patients with B-ALL enrolled in Japan Adult Leukemia Study Group (JALSG) trials. Genomic profiling included whole transcriptome sequencing (RNA-seq), targeted capture (TC) RNA-seq, and TC DNA sequencing. The authors identified 2 novel and distinct subgroups of B-ALL characterized by high CDX2 expression (3.4%, CDX2-high) and IDH1/2 mutations (1.9%, IDH1/2-mut) that were both associated with poor outcome. The promoter of CDX2 was hypomethylated in the CDX2-high group compared with other ALL, leading to outlier high expression. The IDH1/2-mut group was associated with a hypermethylation profile that converged on 23 candidate tumor suppressor genes that may play a role in IDH1/2-induced leukemogenesis.