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

Zhiheng Li^{1

2

3}, Sara Fierstein^{1

2}, Mayuri Tanaka-Yano^{1

2}, Katie Frenis^{1

2}, Chun-Chin Chen^{1

2}, Dahai Wang^{1

2}, Marcelo Falchetti⁴, Parker Côté⁵, Christina Curran^{1

2}, Kate Lu⁵, Tianxin Liu², Stuart Orkin^{2

6

7}, Hojun Li^{5

8}, Edroaldo Lummertz da Rocha⁴, Shaoyan Hu⁹, Qian Zhu^#¹⁰, R Grant Rowe^#^{11

12

13}

Affiliations

¹ Stem Cell Program and Stem Cell Transplantation Programs, Boston Children's Hospital, Boston, MA, USA.
² Department of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
³ Department of Hematology/Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China.
⁴ Federal University of Santa Catarina, Florianopolis, Brazil.
⁵ Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Howard Hughes Medical Institute, Boston, MA, USA.
⁷ Harvard Medical School, Boston, MA, USA.
⁸ Department of Pediatrics, University of California, San Diego, CA, USA.
⁹ Department of Hematology/Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China. hushaoyan@suda.edu.cn.
¹⁰ Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, TX, USA. qian.zhu@bcm.edu.
¹¹ Stem Cell Program and Stem Cell Transplantation Programs, Boston Children's Hospital, Boston, MA, USA. Grant_rowe@dfci.harvard.edu.
¹² Department of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. Grant_rowe@dfci.harvard.edu.
¹³ Harvard Medical School, Boston, MA, USA. Grant_rowe@dfci.harvard.edu.

^# Contributed equally.

PMID: 39354203
DOI: 10.1038/s41375-024-02428-y

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

Zhiheng Li et al. Leukemia. 2025 Jan.

. 2025 Jan;39(1):87-97.

doi: 10.1038/s41375-024-02428-y. Epub 2024 Oct 1.

Authors

Affiliations

¹ Stem Cell Program and Stem Cell Transplantation Programs, Boston Children's Hospital, Boston, MA, USA.
² Department of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA.
³ Department of Hematology/Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China.
⁴ Federal University of Santa Catarina, Florianopolis, Brazil.
⁵ Massachusetts Institute of Technology, Cambridge, MA, USA.
⁶ Howard Hughes Medical Institute, Boston, MA, USA.
⁷ Harvard Medical School, Boston, MA, USA.
⁸ Department of Pediatrics, University of California, San Diego, CA, USA.
⁹ Department of Hematology/Oncology, Children's Hospital of Soochow University, Suzhou, Jiangsu, China. hushaoyan@suda.edu.cn.
¹⁰ Baylor College of Medicine, Department of Molecular and Human Genetics, Houston, TX, USA. qian.zhu@bcm.edu.
¹¹ Stem Cell Program and Stem Cell Transplantation Programs, Boston Children's Hospital, Boston, MA, USA. Grant_rowe@dfci.harvard.edu.
¹² Department of Hematology/Oncology, Boston Children's Hospital, Boston, MA, USA. Grant_rowe@dfci.harvard.edu.
¹³ Harvard Medical School, Boston, MA, USA. Grant_rowe@dfci.harvard.edu.

^# Contributed equally.

PMID: 39354203
DOI: 10.1038/s41375-024-02428-y

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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Conflict of interest statement

Competing interests: The authors declare no competing interests.

References

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

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

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