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MYELODYSPLASTIC NEOPLASM

Whole-genome sequencing of myeloproliferative neoplasms revealed dynamic clonal changes in the fibrotic or leukemic transformation and novel FOXP1 mutations in the fibrotic transformation

Leukemia volume 39, pages 1218–1227 (2025)Cite this article

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Abstract

Myeloproliferative neoplasms (MPNs) are characterized by clonal proliferation of hematopoietic stem cells, which can lead to secondary myelofibrosis or acute myeloid leukemia. We explored the changes in genomic alterations during MPN transformation using whole-genome sequencing of samples from both the chronic and fibrotic or leukemic phases of 20 patients. We identified FOXP1 mutations in 3 of 14 (21.4%) patients with secondary myelofibrosis. This novel mutation was identified in another 5 of the 35 patients (14.3%) in an independent cohort. All these 8 patients with FOXP1 mutations did not experience leukemic transformation after a median follow-up of 5.1 years. The acquisition of non-canonical MPLY591 mutations was detected in the fibrotic or leukemic phase. Clonal expansion, involving both known and unknown driver genes (in 18 and 2 patients, respectively), was observed in all patients. We determined the patterns of clonal evolution based on myeloid driver mutations in 18 patients: linear clonal evolution in 11 patients and branched clonal evolution in 7 patients. Our results suggested that MPN patients carrying FOXP1 mutations are unlikely to have leukemia transformation and emphasized that the acquisition of specific genetic mutations and dynamic changes in clonal architecture underlie the pathogenesis in patients undergoing MPN transformation.

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Fig. 1: Study design and the clinical course of the patients.
Fig. 2: Landscape of the candidate driver mutation in the chronic and fibrotic or leukemic phases.
Fig. 3: Evaluation of MPLY591 (n = 24) and FOXP1 (n = 12) analysis using external cohorts.
Fig. 4: Clonal dynamics of mutations in patients with myeloproliferative neoplasms during the fibrotic or leukemic transformation.

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Data availability

The datasets generated during and analyzed during the current study are available from the corresponding authors on reasonable request. CNA data are available at the following link: https://github.com/HiroyukiTakamori/WGS_MPN_Progression.

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Acknowledgements

The authors acknowledge the patients who participated in the study and their families. The authors thank the clinical research staff and caregivers at all the participating sites. Supercomputing resources were provided by the Human Genome Center, the Institute of Medical Science, the University of Tokyo, Japan.

Funding

This work was supported by grants from the National Science and Technology Council, Taiwan (L-YS: MOST110-2314-B-182-018, MOST111-2314-B-182-043, and NSTC 112-2314-B-182-055), the Ministry of Health and Welfare, Taiwan (L-YS: DOH102-TD-C-111-006), Grant-in-Aid for JSPS KAKENHI (SO: JP19H05656), and the Japan Agency for Medical Research and Development, AMED (YN: 23ama221506h0002).

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Author notes

  1. These authors contributed equally: Hiroyuki Takamori, Ying-Jung Huang.

Authors and Affiliations

  1. Division of Hematopoietic Disease Control, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Hiroyuki Takamori, Hidehito Fukushima, Kazuaki Yokoyama & Yasuhito Nannya

  2. Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan

    Ying-Jung Huang, Ting-Yu Huang, Ming-Chung Kuo & Lee-Yung Shih

  3. School of Medicine, Chang Gung University, Taoyuan, Taiwan

    Ming-Chung Kuo & Lee-Yung Shih

  4. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

    Seishi Ogawa

Authors
  1. Hiroyuki Takamori
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  3. Hidehito Fukushima
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Contributions

L-YS and YN designed and supervised the study. L-YS and Y-JH provided whole- genome sequencing raw data and targeted next generation sequencing data, L-YS and M-CK treated the patients and provided the samples, L-YS, M-CK, and T-YH collected and organized all clinical data. HT, HF, KY, SO, and YN analyzed WGS data. HT, YN, Y-JH and L-YS wrote the manuscript.

Corresponding authors

Correspondence to Yasuhito Nannya or Lee-Yung Shih.

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Competing interests

SO reports a leadership position and advisory role with Eisai Co., Ltd and Chordia Therapeutics, Inc. SO is also a stockholder in Asahi Genomics Co., Ltd., and has received honoraria from The Mitsubishi Foundation and the Nakatani Foundation. Additionally, SO reports receiving grant/research funding from Chordia Therapeutics, Inc., Otsuka Pharmaceutical Co., Ltd., Eisai Co., Ltd, and Nippon Shinyaku Co., Ltd. YN has received grant/research funding from Daiichi Sankyo Co., Ltd., ThinkCyte Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. YN has also received honoraria from Bristol Myers Squibb Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Novartis Pharma Co., Ltd., Pfizer Japan Co., Ltd., Nippon Shinyaku Co., Ltd., Otsuka Pharmaceutical Co., Ltd., and AstraZeneca Co., Ltd. The remaining authors declare no competing financial interests related to this study.

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Takamori, H., Huang, YJ., Fukushima, H. et al. Whole-genome sequencing of myeloproliferative neoplasms revealed dynamic clonal changes in the fibrotic or leukemic transformation and novel FOXP1 mutations in the fibrotic transformation. Leukemia 39, 1218–1227 (2025). https://doi.org/10.1038/s41375-025-02576-9

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