Multipotent lineage potential in B cell acute lymphoblastic leukemia is associated with distinct cellular origins and clinical features

Iacobucci I, Zeng AGX, Gao Q, Garcia-Prat L, Baviskar P, Shah S, Murison A, Voisin V, Chan-Seng-Yue M, Cheng C, Qu C, Bailey C, Lear M, Witkowski MT, Zhou X, Zaldivar Peraza A, Gangwani K, Advani AS, Luger SM, Litzow MR, Rowe JM, Paietta EM, Stock W, Dick JE, Mullighan CG. Multipotent lineage potential in B cell acute lymphoblastic leukemia is associated with distinct cellular origins and clinical features. Nat Cancer. 2025 Jul;6(7):1242-1262. doi: 10.1038/s43018-025-00987-2. Epub 2025 Jun 27. PMID: 40579588; PMCID: PMC12377259.

Developmental origins and their associations with lineage plasticity and treatment response in B-cell progenitor acute lymphoblastic leukemia (B-ALL) are mostly unexplored. Here, we integrated single-cell transcriptome sequencing (scRNA-seq) of 89 B-ALL samples with a single-cell atlas of normal human B cell development incorporating functional and molecular assays. We observed subtype- and sample-dependent correlation with normal developmental stage, with intra-subtype and intra-patient heterogeneity. We show that subtypes prone to shift from the B-lineage (for example BCR::ABL1, KMT2A-R and DUX4-R B-ALL) are enriched for multipotent progenitors and show this developmental stage exhibits CEBPA activation and retains myeloid potential, providing a mechanistic explanation for this clinical observation. We developed a ‘multipotency score’ most enriched in subtypes exhibiting lineage plasticity that was independently associated with inferior survival. Thus, multipotent B-ALL states reflect the early progenitor origins of a subset of patients with B-ALL and may be relevant for understanding lineage shifting following conventional chemotherapy or immunotherapies.