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<p>Paroxysmal nocturnal hemoglobinuria (PNH) originates from hematopoietic stem cells (HSCs) harboring somatic mutations in the phosphatidylinositol glycan class A (<i>PIGA</i>) gene. Clonal expansion of <i>PIGA</i>-mutated cells occurs uniquely in the setting of bone marrow (BM) failure, but specific pathophysiologic mechanisms remain unclear. We performed single-cell RNA sequencing (scRNA-seq) of BM cells from patients with large (&gt; 50%) and small (10–50%) PNH cell fractions. In patients with large PNH cell fractions, phenotypically normal hematopoietic stem and progenitor cells (HSPCs) upregulated immune response and apoptosis pathways and downregulated cell-cycling pathways compared with PNH-type HSPCs. BM effector cells upregulated immune response pathways, and cell-cell communication between effector cells and normal HSPCs was greater than in controls. In contrast, in patients with small PNH cell fractions, transcriptional changes in normal HSPCs were reversed: downregulation of immune response pathways and upregulation of the cell-cycling pathways. Notably, transcriptional differences associated with PNH cell fractions were primarily in normal HSCs, whereas PNH-type HSCs showed similar transcriptional profiles between patients with large and small PNH cell fractions. These results implicate immunological negative selection against normal HSCs in PNH. Error-corrected DNA sequencing of patients’ blood samples identified multiple <i>PIGA</i> mutations in each patient, consistent with strong selection for the resulting phenotype.</p>

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Imputing causality and clonal dynamics from single-cell transcriptomics in paroxysmal nocturnal hemoglobinuria

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月22日

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  • Hiroki Mizumaki,
  • Shouguo Gao,
  • Zhijie Wu,
  • Fernanda Gutierrez-Rodrigues,
  • Lemlem Alemu,
  • Diego Quinones Raffo,
  • Ivana Darden,
  • Olga Rios,
  • Jennifer Lotter,
  • Sachiko Kajigaya,
  • Jibran Durrani,
  • Emma M. Groarke,
  • Bhavisha A. Patel,
  • Neal S. Young

摘要

Paroxysmal nocturnal hemoglobinuria (PNH) originates from hematopoietic stem cells (HSCs) harboring somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene. Clonal expansion of PIGA-mutated cells occurs uniquely in the setting of bone marrow (BM) failure, but specific pathophysiologic mechanisms remain unclear. We performed single-cell RNA sequencing (scRNA-seq) of BM cells from patients with large (> 50%) and small (10–50%) PNH cell fractions. In patients with large PNH cell fractions, phenotypically normal hematopoietic stem and progenitor cells (HSPCs) upregulated immune response and apoptosis pathways and downregulated cell-cycling pathways compared with PNH-type HSPCs. BM effector cells upregulated immune response pathways, and cell-cell communication between effector cells and normal HSPCs was greater than in controls. In contrast, in patients with small PNH cell fractions, transcriptional changes in normal HSPCs were reversed: downregulation of immune response pathways and upregulation of the cell-cycling pathways. Notably, transcriptional differences associated with PNH cell fractions were primarily in normal HSCs, whereas PNH-type HSCs showed similar transcriptional profiles between patients with large and small PNH cell fractions. These results implicate immunological negative selection against normal HSCs in PNH. Error-corrected DNA sequencing of patients’ blood samples identified multiple PIGA mutations in each patient, consistent with strong selection for the resulting phenotype.