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<p>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 <i>BCR::ABL1</i>, <i>KMT2A</i>-R and <i>DUX4</i>-R B-ALL) are enriched for multipotent progenitors and show this developmental stage exhibits <i>CEBPA</i> 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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年6月27日

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  • Ilaria Iacobucci,
  • Andy G. X. Zeng,
  • Qingsong Gao,
  • Laura Garcia-Prat,
  • Pradyumna Baviskar,
  • Sayyam Shah,
  • Alex Murison,
  • Veronique Voisin,
  • Michelle Chan-Seng-Yue,
  • Cheng Cheng,
  • Chunxu Qu,
  • Colin Bailey,
  • Matthew Lear,
  • Matthew T. Witkowski,
  • Xin Zhou,
  • Airen Zaldivar Peraza,
  • Karishma Gangwani,
  • Anjali S. Advani,
  • Selina M. Luger,
  • Mark R. Litzow,
  • Jacob M. Rowe,
  • Elisabeth M. Paietta,
  • Wendy Stock,
  • John E. Dick,
  • Charles G. Mullighan

摘要

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.