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ACUTE MYELOID LEUKEMIA

Longitudinal single-cell analysis reveals treatment-resistant stem and mast cells with potential treatments for pediatric AML

Leukemia (2025)Cite this article

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A Correction to this article was published on 19 September 2025

This article has been updated

Abstract

Pediatric acute myeloid leukemia (pAML) is a heterogeneous malignancy driven by diverse cytogenetic mutations. While identification of cytogenetic lesions improved risk stratification, prognostication remains inadequate with 30% of standard-risk patients experiencing relapse within 5 years. To deeply characterize pAML heterogeneity and identify poor outcome-associated blast cell profiles, we performed an analysis on 708,285 cells from 164 bone marrow biopsies of 95 patients and 11 healthy controls. The longitudinal analysis on cell abundances at the time of disease diagnosis, end of induction, and relapse identified treatment resistant stem-like blast cells specific to RUNX1::RUNX1T1, FLT3-ITD, and CBFB::MYH11 patients that are associated with poor outcomes. Treatment resistant blast cells from RUNX1::RUNX1T1 were found to associate with T cell exhaustion, while those from FLT-ITD utilized enriched antioxidant metabolism to persist through treatment. Interestingly, the analysis also identified novel mast cell-like pAML associated with treatment resistance and poor outcomes. Deconvolution of ex vivo treatment data and subsequent in vitro validation identified bortezomib (RUNX1), ponatinib, and venetoclax (FLT3) as specifically potent against treatment resistant blasts from the respective cytogenetic groups. Our findings indicate immature and mature pAML subtypes are promising biomarkers for enhanced patient risk stratification and identifies targeted agents to increase their clearance after treatment.

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Fig. 1: Schematic for analysis of pediatric acute myeloid leukemia datasets to identify and characterize high-risk, treatment-resistant subtypes.
Fig. 2: Malignant blast cell identification.
Fig. 3: Analysis of malignant cells from longitudinal diagnosis, end-of-induction, and relapse samples reveals treatment-resistant cell types.
Fig. 4: High-risk, treatment-resistant cells in RUNX1 pediatric acute myeloid leukemia (pAML) are proliferative, anti-apoptotic, and immune effectors.
Fig. 5: High-risk, treatment-resistant hematopoietic stem cell (HSC)-like cells in RUNX1 patients promote an inflammatory, exhausted immune microenvironment.
Fig. 6: High-risk, treatment-resistant HSC-like cells in FLT3 patients express leukemic stem cell markers and utilize antioxidant metabolism.
Fig. 7: Core binding factor (CBF) mutated pAML patients depict elevated mast cells associated with poor outcomes.

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Data availability

The data used in this manuscript are available in the publicly available Gene Expression Omnibus (NCBI GEO) under accession numbers GSE235923, GSE235063, GSE154109, GSE185381, and ScPCA (https://scpca.alexslemonade.org/). Code used in this manuscript will be made available upon reasonable request to the corresponding author.

Code availability

The data used in this manuscript are available in the publicly available Gene Expression Omnibus (NCBI GEO) under accession numbers GSE235923, GSE235063, GSE154109, GSE185381, and ScPCA (https://scpca.alexslemonade.org/). Code used in this manuscript will be made available upon reasonable request to the corresponding author.

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Acknowledgements

The study is supported through translational award from the CURE Childhood Foundation (Ma.B.) and Emory startup funds (Ma.B.).

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Authors and Affiliations

  1. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA, USA

    Denis Ohlstrom, Alejandro De Janon Gutierrez, Katherine E. Ferguson & William Pilcher

  2. Emory University School of Medicine, Atlanta, GA, USA

    Denis Ohlstrom

  3. Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Atlanta, GA, USA

    Mojtaba Bakhtiari, Alejandro De Janon Gutierrez, Deborah DeRyckere, Douglas Graham, Swati Bhasin & Manoj Bhasin

  4. Department of Pediatrics, Emory University, Atlanta, GA, USA

    Mojtaba Bakhtiari, Deborah DeRyckere, Frank Chien, Swati Bhasin & Manoj Bhasin

  5. Department of Biomedical Informatics, Emory University, Atlanta, GA, USA

    Hope Mumme, Marina Michaud, Sarthak Satpathy, Sean Jordan & Manoj Bhasin

  6. Winship Cancer Institute, Emory University, Atlanta, GA, USA

    Manoj Bhasin

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  1. Denis Ohlstrom
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Contributions

Conceptualization DO, MoB, HM, MM, ADJG, DD, KEF, FC, WP, SS, SJ, DG, SB, MaB; Methodology DO, HM, MM, ADJG, DD, DG, MaB; Formal Analysis DO; Investigation MoB, ADJG; Data Curation DO, HM; Writing – Original Draft DO; Writing – Reviewing & Editing DO, MoB, HM, MM, ADJG, DD, KF, FC, WP, SS, SJ, DG, SB, MaB; Visualization DO, MoB; Supervision MaB; Funding Acquisition MaB.

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Correspondence to Manoj Bhasin.

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The authors declare no competing interests.

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All methods in this study were performed in accordance with the relevant guidelines and regulations. Single-cell RNA sequencing data sets were procured from publicly available repositories. Informed consent and institutional review board approval were obtained in the respective studies [6,7,8,9]. Ex vivo drug sensitivity studies were performed under informed consent and institutional review board approval (Emory University IRB #00034535).

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The original online version of this article was revised: In this article the author’s name Mojtaba Bakhtiari was incorrectly written as Mojtaba Bakhtia. The original article has been corrected.

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Ohlstrom, D., Bakhtiari, M., Mumme, H. et al. Longitudinal single-cell analysis reveals treatment-resistant stem and mast cells with potential treatments for pediatric AML. Leukemia (2025). https://doi.org/10.1038/s41375-025-02748-7

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