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<p>The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal hematopoiesis is not well defined. We conducted whole-genome sequencing on 1,276 single-cell-derived hematopoietic stem and progenitor cell (HSPC) colonies from ten patients with multiple myeloma treated with chemotherapies and six normal donors. Melphalan treatment significantly increased the mutational burden, producing a distinctive mutation signature, whereas other chemotherapeutic agents had minimal effects. Consequently, the clonal diversity and architecture of post-treatment HSPCs resemble those observed in normal elderly individuals, particularly through the progression of oligoclonal hematopoiesis, thereby suggesting that chemotherapy accelerates clonal aging. Integrated phylogenetic analysis of matched therapy-related myeloid neoplasm samples traced their clonal origin to a single-HSPC clone among multiple competing clones, supporting a model of oligoclonal to monoclonal transformation. These findings underscore the need for further systematic research on the long-term hematological consequences of cancer chemotherapy.</p>

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Clonal evolution of hematopoietic stem cells after autologous stem cell transplantation

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月1日

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  • Hidetaka Uryu,
  • Koichi Saeki,
  • Hiroshi Haeno,
  • Chiraag Deepak Kapadia,
  • Ken Furudate,
  • Jyoti Nangalia,
  • Michael Spencer Chapman,
  • Linda Zhang,
  • Jennifer Padilla,
  • Li Zhao,
  • Joanne I. Hsu,
  • Chong Zhao,
  • Shujuan Chen,
  • Tomoyuki Tanaka,
  • Zongrui Li,
  • Satoko Ogata,
  • Sarah Hanache,
  • Hui Yang,
  • Courtney DiNardo,
  • Naval Daver,
  • Naveen Pemmaraju,
  • Nitin Jain,
  • Farhad Ravandi,
  • Jianhua Zhang,
  • Xingzhi Song,
  • Erika Thompson,
  • Hongli Tang,
  • Latasha Little,
  • Curtis Gumbs,
  • Robert Z. Orlowski,
  • Muzaffar Qazilbash,
  • Kapil Bhalla,
  • Simona Colla,
  • Hagop Kantarjian,
  • Rashmi Kanagal-Shamanna,
  • Carlos Bueso-Ramos,
  • Daisuke Nakada,
  • Gheath Al-Atrash,
  • Jeffery Molldrem,
  • P. Andrew Futreal,
  • Elizabeth Shpall,
  • Margaret Goodell,
  • Guillermo Garcia-Manero,
  • Koichi Takahashi

摘要

The impact of exogenous stressors, such as cancer chemotherapies, on the genomic integrity and clonal dynamics of normal hematopoiesis is not well defined. We conducted whole-genome sequencing on 1,276 single-cell-derived hematopoietic stem and progenitor cell (HSPC) colonies from ten patients with multiple myeloma treated with chemotherapies and six normal donors. Melphalan treatment significantly increased the mutational burden, producing a distinctive mutation signature, whereas other chemotherapeutic agents had minimal effects. Consequently, the clonal diversity and architecture of post-treatment HSPCs resemble those observed in normal elderly individuals, particularly through the progression of oligoclonal hematopoiesis, thereby suggesting that chemotherapy accelerates clonal aging. Integrated phylogenetic analysis of matched therapy-related myeloid neoplasm samples traced their clonal origin to a single-HSPC clone among multiple competing clones, supporting a model of oligoclonal to monoclonal transformation. These findings underscore the need for further systematic research on the long-term hematological consequences of cancer chemotherapy.