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<p>Aplastic anemia (AA) results from T-cell-mediated destruction of hematopoietic stem and progenitor cells (HSPCs), driving clonal hematopoiesis via loss of human leukocyte antigen (HLA) risk alleles (HLA loss-of-function mutations or uniparental disomy 6p, UPD6p), paroxysmal nocturnal hemoglobinuria and clonal hematopoiesis of indeterminate potential (CHIP) mutations. Here genomic profiling of 619 patients with AA revealed clonal hematopoiesis in 69% of cases, with <i>ASXL1</i>, <i>BCOR</i> and <i>BCORL1</i> identified as the most frequent CHIP mutations in pediatric cases. Single-cell multi-omics analysis of 304,902 cells from 48 samples uncovered complex branching clonal architecture, with a median of three HLA loss events per patient, converging to inactivate HLA risk alleles. Single-cell whole-genome sequencing (WGS) resolved up to 15 HLA loss clones per patient and phylogenetic reconstruction indicated that these clones originated years before diagnosis. Long-read WGS precisely mapped UPD6p breakpoints and HLA methylation. HLA loss conferred a protective effect against CHIP, evidenced by their near-absent co-occurrence. Longitudinal single-cell analysis demonstrated that long-lived clones were enriched in the CD34<sup>+</sup> HSPC compartment. These findings reveal parallel evolutionary pathways used by hematopoietic cells to evade immune attack.</p>

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High-resolution single-cell mapping of clonal hematopoiesis and structural variation in aplastic anemia

  • 期刊论文

  • 发表日期：

    2026年5月1日

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  • Masanori Yoshida,
  • Sushree S. Sahoo,
  • Paula Y. Arnold,
  • Carmelo Gurnari,
  • Anaïs J. C. N. van Leeuwen,
  • Limeng Pu,
  • Markus J. van Roosmalen,
  • Ti-Cheng Chang,
  • Charnise Goodings,
  • Rashid Mehmood,
  • Lucca L. M. Derks,
  • Nathan Gray,
  • Michelle Boals,
  • Sara Lewis,
  • Lili Kotmayer,
  • Cristyn N. Branstetter,
  • Swapna Thota,
  • Joshua Leow,
  • Wenchao Zhang,
  • Yichao Li,
  • Melanie R. Loyd,
  • Granger Ridout,
  • Emily V. Walker,
  • Christy W. LaFlamme,
  • Heather C. Mefford,
  • Zachary Brady,
  • Yash B. Shah,
  • Rheanna G. Congdon,
  • Miriam Erlacher,
  • Brigitte Strahm,
  • Ayami Yoshimi,
  • Shinsuke Hirabayashi,
  • Helen D. Reed,
  • Akiko Shimamura,
  • Guolian Kang,
  • Xiang Chen,
  • Jinghui Zhang,
  • Charlotte M. Niemeyer,
  • Joseph H. Oved,
  • Timothy S. Olson,
  • Ruben van Boxtel,
  • Jaroslaw P. Maciejewski,
  • Daria V. Babushok,
  • Marcin W. Wlodarski

摘要

Aplastic anemia (AA) results from T-cell-mediated destruction of hematopoietic stem and progenitor cells (HSPCs), driving clonal hematopoiesis via loss of human leukocyte antigen (HLA) risk alleles (HLA loss-of-function mutations or uniparental disomy 6p, UPD6p), paroxysmal nocturnal hemoglobinuria and clonal hematopoiesis of indeterminate potential (CHIP) mutations. Here genomic profiling of 619 patients with AA revealed clonal hematopoiesis in 69% of cases, with ASXL1, BCOR and BCORL1 identified as the most frequent CHIP mutations in pediatric cases. Single-cell multi-omics analysis of 304,902 cells from 48 samples uncovered complex branching clonal architecture, with a median of three HLA loss events per patient, converging to inactivate HLA risk alleles. Single-cell whole-genome sequencing (WGS) resolved up to 15 HLA loss clones per patient and phylogenetic reconstruction indicated that these clones originated years before diagnosis. Long-read WGS precisely mapped UPD6p breakpoints and HLA methylation. HLA loss conferred a protective effect against CHIP, evidenced by their near-absent co-occurrence. Longitudinal single-cell analysis demonstrated that long-lived clones were enriched in the CD34+ HSPC compartment. These findings reveal parallel evolutionary pathways used by hematopoietic cells to evade immune attack.