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<p>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.</p>

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Chromatin accessibility in stem cells unveils progressive transcriptional alterations in myelodysplastic syndrome

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • Motohiko Oshima,
  • Naoya Takayama,
  • Yaeko Nakajima-Takagi,
  • Daisuke Shinoda,
  • Naoki Itokawa,
  • Shuhei Kurosawa,
  • Satoshi Kaito,
  • Takahiro Kamiya,
  • Yuta Yamada,
  • Shohei Andoh,
  • Kensuke Kayamori,
  • Sudip Kumar Paul,
  • Maria Alejandra Kanashiro,
  • Tomoya Muto,
  • Shokichi Tsukamoto,
  • Emiko Sakaida,
  • Eriko Sato,
  • Nozomi Yusa,
  • Kazuaki Yokoyama,
  • Yasuhito Nannya,
  • Seiya Imoto,
  • Bahityar Rahmutulla,
  • Atsushi Kaneda,
  • Kiyoshi Yamaguchi,
  • Yoichi Furukawa,
  • Noriko Doki,
  • Koji Eto,
  • Kei Nishikawa,
  • Ye Ding,
  • Tomohiro Myojo,
  • Yuka Harada,
  • Hironori Harada,
  • Atsushi Iwama

摘要

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.