Molecular complexity of DS-ALL. Li et al identified 15 molecular subtypes, with 3 significantly novel subtypes enriched in DS-ALL compared with non-DS ALL (ratios shown in parentheses under subtype labels). CRLF2r, commonly resulting from IGH::CRLF2 translocations or P2RY8::CRLF2 microdeletions, leads to CRLF2 overexpression and activation of the JAK/STAT or RAS/MAPK signaling pathway, promoting pro–B-cell proliferation. Although CRLF2r is a signature event of a Ph-like subtype, this large DS-ALL cohort reveals further heterogeneity based on GEP, with Ph–like CRLF2r cases having worse clinical outcomes than non–Ph-like group. Another novel subtype is characterized by C/EBP gene family activation, primarily involving the CEBPD gene through genomic translocations (often with the IGHJ region) or enhancer hijacking mutations. This subtype displays a unique GEP, higher mutation rates in SETD2, KDM6A, and FLT3 genes, and intermediate risk levels. CEBPD overexpression promotes hematopoietic progenitor cell differentiation into pro-B cells, particularly in a cT21 genetic background. A minor subtype, characterized by IGHJ::IGF2BP1 gene rearrangement likely through RAG-mediated structural changes near RSS regions, has a relatively favorable clinical outcome. Although no distinct GEP is observed for this subtype, some cases share a similar GEP with the ETV6::RUNX1 subtype, potentially because of IGF2BP1 overexpression in ETV6::RUNX1 subtype resulting from ETV6 loss, which normally represses IGF2BP1 expression. The observed function of IGF2BP1 in stabilizing ETV6::RUNX1 messenger RNA further supports the potential association between these 2 genetic alterations in ALL. However, as ETV6::RUNX1 messenger RNA is not expressed in DS-ALL, the role of IGF2BP1 in DS-ALL remains unknown. ALL, acute lymphoblastic leukemia; CRLF2r, CRLF2 rearrangement; GEP, gene expression profile; RAG, recombination-activating gene; RSS, recombination signal sequences.