Disease subtypes identified in AYA and adults with B-ALL. (A) Gene expression profiling of 323 cases of Ph^– B-ALL and 28 control samples (Ph⁺ALL; n = 4, T-cell ALL [T-ALL]; n = 18, normal lymphocyte; n = 6) in a 2-dimensional, t-distributed, stochastic neighbor embedding plot with a perplexity score of 15. We used a previously reported gene set (n = 200)¹⁴ for analysis (see supplemental Methods).¹⁵ Major subtypes defined by rearrangements (ZNF384, TCF3-PBX1, DUX4, MEF2D, KMT2A, and BCL2/MYC) and gross chromosomal alterations (HeH and HoL), as well as control samples (Ph⁺ ALL, T-ALL, and normal lymphocyte), are colored in each group. Ph-like, PAX5alt, PAX5 P80R, and CEBP/ZEB2 subtypes, which were defined using hierarchical clustering (supplemental Figure 2A,B), are also shown. Gray dots indicate other B-ALL. We propose 2 novel subtypes with distinct expression profiles: CDX2-high and IDH1/2-mut subtypes. (B) Distribution of Ph^– B-ALL subtypes between AYA (15 to 39 years old) and adults (40 to 64 years old), whose samples were subjected to RNA-seq (n = 323). (C) The landscape of genetic alterations for 262 cases of the 18 indicated subtypes, identified by TC-DNA-seq. Rearrangements, common gene alterations (n ≥ 8), mutations in key genes (IL7R, CRLF2, and IDH1/2), and common arm-level CNVs are shown. Clinical information and information on the implementation status of NGS (RNA-seq and TC-RNA-seq) are also provided. Clonality indicates immunoglobulin rearrangements. NH, near haploid.