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ACUTE MYELOID LEUKEMIA

The epigenetic state of the cell of origin defines mechanisms of leukemogenesis

Leukemia volume 39, pages 87–97 (2025)Cite this article

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Abstract

Acute myeloid leukemia (AML) shows variable clinical outcome. The normal hematopoietic cell of origin impacts the clinical behavior of AML, with AML from hematopoietic stem cells (HSCs) prone to chemotherapy resistance in model systems. However, the mechanisms by which HSC programs are transmitted to AML are not known. Here, we introduce the leukemogenic MLL-AF9 translocation into defined human hematopoietic populations, finding that AML from HSCs is enriched for leukemic stem cells (LSCs) compared to AML from progenitors. By epigenetic profiling, we identify a putative inherited program from the normal HSC that collaborates with oncogene-driven programs to confer aggressive behavior in HSC-AML. We find that components of this program are required for HSC-AML growth and survival and identify RNA polymerase (RNAP) II-mediated transcription as a therapeutic vulnerability. Overall, we propose a mechanism as to how epigenetic programs from the leukemic cell of origin are inherited through transformation to impart the clinical heterogeneity of AML.

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Fig. 1: Generating AML of defined cellular origin by engineering the MLL-AF9 translocation in human HSPCs.
Fig. 2: Retention of stemness programs in HSC leukemia.
Fig. 3: Defining the global MLL-AF9-driven and -independent epigenome of AMLs of defined cellular origin.
Fig. 4: AML dependencies identified in the HSC-AML epigenetic program.
Fig. 5: Vulnerability of HSC AML to transcriptional inhibition and perturbation of mRNA splicing.

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Data availability

Sequencing data are available in Gene Expression Omnibus (GSE262561).

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Acknowledgements

This work was supported by the V Foundation, the National Institute for Diabetes, Digestive, and Kidney Disorders (R01DK134515), the Department of Defense (W81XWH2110301 and Convergent Science Virtual Cancer Center Director’s Award Pilot for Expanded Research), and the South Shore Action for Hope (to R.G.R.).

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Author notes

  1. These authors contributed equally: Qian Zhu, R. Grant Rowe.

Authors and Affiliations

  1. Stem Cell Program and Stem Cell Transplantation Programs, Boston Children’s Hospital, Boston, MA, USA

    Zhiheng Li, Sara Fierstein, Mayuri Tanaka-Yano, Katie Frenis, Chun-Chin Chen, Dahai Wang, Christina Curran & R. Grant Rowe

  2. Department of Hematology/Oncology, Boston Children’s Hospital, Boston, MA, USA

    Zhiheng Li, Sara Fierstein, Mayuri Tanaka-Yano, Katie Frenis, Chun-Chin Chen, Dahai Wang, Christina Curran, Tianxin Liu, Stuart Orkin & R. Grant Rowe

  3. Department of Hematology/Oncology, Children’s Hospital of Soochow University, Suzhou, Jiangsu, China

    Zhiheng Li & Shaoyan Hu

  4. Federal University of Santa Catarina, Florianopolis, Brazil

    Marcelo Falchetti & Edroaldo Lummertz da Rocha

  5. Massachusetts Institute of Technology, Cambridge, MA, USA

    Parker Côté, Kate Lu & Hojun Li

  6. Howard Hughes Medical Institute, Boston, MA, USA

    Stuart Orkin

  7. Harvard Medical School, Boston, MA, USA

    Stuart Orkin & R. Grant Rowe

  8. Department of Pediatrics, University of California, San Diego, CA, USA

    Hojun Li

  9. Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, TX, USA

    Qian Zhu

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  1. Zhiheng Li
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Contributions

Z.L., S.F., M.T., K.F., C-C.C., C.C., and D.W. performed research, M.F., P.C., K.L., T.L., and Q.Z. performed analysis of CUT&RUN and transcriptomic data, S.O., H.L., E.L.d.R., S.H., Q.Z., and R.G.R supervised research. R.G.R. wrote the manuscript.

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Correspondence to Shaoyan Hu, Qian Zhu or R. Grant Rowe.

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Li, Z., Fierstein, S., Tanaka-Yano, M. et al. The epigenetic state of the cell of origin defines mechanisms of leukemogenesis. Leukemia 39, 87–97 (2025). https://doi.org/10.1038/s41375-024-02428-y

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