Chromatin accessibility in stem cells unveils progressive transcriptional alterations in myelodysplastic syndrome
Myelodysplastic syndrome (MDS) originates from hematopoietic stem cell (HSC) clones with acquired gene mutations. However, the molecular characteristics of MDS stem cells remain poorly understood. Here, we show that the chromatin accessibility profiles of MDS stem cells more accurately reflect disease status than those of progenitor cells and reveal the process of stem cell alterations during disease progression. Characterization of differentially accessible regions (DARs) shows that MDS stem cells acquire progenitor-like chromatin accessibility during disease progression, leading to disruption of the normal stem-progenitor hierarchy. Profiling of transcription factor-binding motifs at DARs further uncovers precocious activation of myeloid transcriptional networks in MDS stem cells, with a concurrent loss of HSC-associated regulatory programs. In particular, increased chromatin accessibility at CEBP target sites represents the myeloid reprogramming status of MDS stem cells. Newly developed "progenitor scores" based on chromatin accessibility stratify disease status and correlate well with prognosis. These findings indicate that chromatin landscapes of MDS stem cells define their cell-autonomous behavior and contribute to disease progression.
Authors
- Yaeko Nakajima-Takagi
- Bahityar Rahmutulla (ORCID: https://orcid.org/0000-0002-4014-2789)
- Kiyoshi Yamaguchi (ORCID: https://orcid.org/0000-0003-2113-4369)
- Yoichi Furukawa (ORCID: https://orcid.org/0000-0003-0462-8631)
- Kensuke Kayamori (ORCID: https://orcid.org/0000-0001-6140-3135)
- Naoki Itokawa (ORCID: https://orcid.org/0000-0002-2091-4948)
- Kazuaki Yokoyama (ORCID: https://orcid.org/0000-0002-2556-3833)
- Emiko Sakaida (ORCID: https://orcid.org/0000-0002-7254-1928)
- Atsushi Iwama (ORCID: https://orcid.org/0000-0001-9410-8992)
- Koji Eto (ORCID: https://orcid.org/0000-0002-5863-7122)
- Noriko Doki (ORCID: https://orcid.org/0000-0002-8661-3179)
- Hironori Harada (ORCID: https://orcid.org/0000-0001-9401-5470)
- Shokichi Tsukamoto (ORCID: https://orcid.org/0000-0003-4314-893X)
- Shohei Andoh
- Tomohiro Myojo
- Kei Nishikawa (ORCID: https://orcid.org/0000-0002-7718-7606)
- Sudip Kumar Paul (ORCID: https://orcid.org/0009-0000-3131-0042)
- Shuhei Kurosawa (ORCID: https://orcid.org/0000-0001-6426-6770)
- Yasuhito Nannya (ORCID: https://orcid.org/0000-0002-6526-0992)
- Yuta Yamada (ORCID: https://orcid.org/0000-0002-9698-4301)
- Yuka Harada (ORCID: https://orcid.org/0000-0002-4550-3176)
- Takahiro Kamiya (ORCID: https://orcid.org/0000-0003-3080-3747)
- Satoshi Kaito (ORCID: https://orcid.org/0000-0001-7966-291X)
- Atsushi Kaneda (ORCID: https://orcid.org/0000-0002-6980-5515)
- Motohiko Oshima (ORCID: https://orcid.org/0000-0001-6991-815X)
- Maria Alejandra Kanashiro (ORCID: https://orcid.org/0009-0006-0689-9717)
- Seiya Imoto (ORCID: https://orcid.org/0000-0002-2989-308X)
- Eriko Sato (ORCID: https://orcid.org/0000-0003-4159-2834)
- Naoya Takayama (ORCID: https://orcid.org/0000-0001-6867-1677)
- Ye Ding (ORCID: https://orcid.org/0000-0003-3460-1122)
- Daisuke Shinoda
- Nozomi Yusa
- Tomoya Muto
Institutions
- Tokyo University of Pharmacy and Life Sciences (JP)
- Chiba University (JP)
- Tokyo Metropolitan Komagome Hospital (JP)
- Chiba University Hospital (JP)
- Tokyo Medical University Hospital (JP)
- University of Tokyo Hospital (JP)
- Edogawa Hospital (JP)
- Juntendo University Nerima Hospital (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-11-28
- DOI
- https://doi.org/10.1038/s41467-025-65753-5
- Citations
- 1
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 1.77
Funders
- Japan Agency for Medical Research and Development
- Japan Society for the Promotion of Science
- Institute of Medical Science, University of Tokyo
- Moonshot Research and Development Program