Pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL)—a cancer of the blood and bone marrow —can sometimes relapse with features of both B-ALL and a different type of blood cancer, acute myeloid leukemia (AML). In a study published in Nature Cancer, UHN’s Dr. John Dick at Princess Margaret Cancer Centre and Dr. Charles Mullighan at St. Jude Children’s Research Hospital investigated the ability of cells to change from one type to another in B-ALL, and how it affects treatment response.
B-ALL is characterized by the abnormal proliferation of immature lymphoid cells—immune cells that develop into specific types of white blood cells, such as B lymphocytes (B-cells). Categorizing patients into B-ALL subtypes and identifying associated risk levels can predict treatment response and likelihood of relapse. Although pediatric B-ALL cure rates have improved, high-risk children still face poor outcomes, and relapse remains a major cause of death.
Evidence suggests that B-ALL can switch from lymphoid to myeloid lineages after certain immunotherapies or chemotherapy. This phenomenon occurs when a cancerous cell originally classified as lymphoid (e.g., a B-cell precursor) transforms into a myeloid-like cell, such as a granulocyte or macrophage precursor. Malignancies in these lineages lead to different blood cancers, such as ALL from lymphoid cells and AML from myeloid cells. ALL and AML have different molecular features and require different treatment targets.
These findings underscore the importance of understanding B-cell development and lineage switching to predict treatment response. To achieve this, the team analyzed the active and expressed genes (i.e., the transcriptome) of individual leukemia cells from 89 B-ALL patient samples and compared them to normal human B-cell development. To do this, they developed the first comprehensive single-cell reference atlas of normal human B-cell development, spanning over 100,000 cells from various tissue sources.
In constructing this atlas, they discovered that a population of stem cells previously thought to only be capable of producing lymphoid cells (such as B cells) had the hidden ability to produce myeloid cells in the experimental setting.
The researchers found that some B-ALL patient samples contained leukemia cells that highly resemble this population of stem cells with myeloid potential. B-ALL patients who had more of these specific leukemia cells were also more likely to have genomic alterations associated with lineage shifts from lymphoid leukemia to myeloid leukemia at disease relapse.
“Some of these immature lymphoid cells can still develop into myeloid cells,” says Dr. Dick, Senior Scientist at the Princess Margaret Cancer Centre. “This ability, called multipotency, may explain the transition from ALL cases to AML in response to B-cell-specific immunotherapy.”
"We developed a Multipotency Score to describe the abundance of multipotent leukemic cells in patient samples. This score can help predict clinical outcomes,” says Dr. Andy Zeng, co-first author of the study. When tested in independent B-ALL patient datasets, a higher Multipotency Score was associated with higher-risk disease and older age. A high score in pediatric patients was also found to be linked to chemo-resistance and worse overall survival.
“Our research advances our understanding of normal and cancerous B-cell development, which may ultimately enhance risk stratification and therapy development for B-ALL patients,” says Dr. Mullighan, co-corresponding author of the study.
Dr. John Dick, Senior Scientist at Princess Margaret Cancer Centre (PM) and Professor of Molecular Genetics at the University of Toronto (U of T) is a co-senior author of the study. Dr. Dick is also the Helga and Antonio De Gasperis Chair in Blood Cancer Stem Cell Research.
Dr. Charles Mullighan, Co-leader of the Hematological Malignancies Program of the St. Jude Comprehensive Cancer Center is co-senior author of the study.
The co-first authors of the study are Dr. Ilaria Iacobucci, Staff Scientist at St. Jude Children’s Hospital; Dr. Andy Zeng, MD/PhD Candidate at PM and the Temerty Faculty of Medicine at U of T and recent Doctoral Graduate; Dr. Qingsong Gao, Research Scientist at St. Jude Children’s Hospital; and Dr. Laura Garcia-Prat, former Postdoctoral Researcher at UHN and currently a Senior Scientist at Cimeio Therapeutics.
This work was supported by The Princess Margaret Cancer Foundation, St. Jude Children's Research Hospital - ALSAC, the Canadian Institutes of Health Research, National Cancer Institute, Ontario Institute for Cancer Research, International Development Research Centre, Canadian Cancer Society, Terry Fox Research Institute, University of Toronto, University of Toronto’s Medicine by Design, Ontario Government, Alex’s Lemonade Stand Foundation, St. Baldrick's Foundation, Southwest Oncology Group National Clinical Trials Network, and the Henry Schueler 41&9 Foundation.
Ilaria Iacobucci reported consultation honoraria from Arima and travel expenses from Mission Bio and Takara. Charles G. Mullighan received research funding from AbbVie and Pfizer, honoraria from Amgen and Illumina, and royalty payments from Cyrus. He is on an advisory board for Illumina. John E. Dick received research funding from BMS/Celgene and IP licenses from Pfizer/Trillium Therapeutics. For other competing interests, see the manuscript.
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 Jun 27. doi: 10.1038/s43018-025-00987-2