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Clonal expansion of\n                    <jats:italic>PIGA<\/jats:italic>\n                    -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;\u200950%) and small (10\u201350%) 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\u2019 blood samples identified multiple\n                    <jats:italic>PIGA<\/jats:italic>\n                    mutations in each patient, consistent with strong selection for the resulting phenotype.\n                  <\/jats:p>","DOI":"10.1038\/s41375-026-02914-5","type":"journal-article","created":{"date-parts":[[2026,4,22]],"date-time":"2026-04-22T11:31:25Z","timestamp":1776857485000},"page":"1368-1380","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Imputing causality and clonal dynamics from single-cell transcriptomics in paroxysmal nocturnal hemoglobinuria"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9933-4638","authenticated-orcid":false,"given":"Hiroki","family":"Mizumaki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shouguo","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhijie","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3116-4588","authenticated-orcid":false,"given":"Fernanda","family":"Gutierrez-Rodrigues","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lemlem","family":"Alemu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diego","family":"Quinones Raffo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivana","family":"Darden","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Rios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jennifer","family":"Lotter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachiko","family":"Kajigaya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jibran","family":"Durrani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4648-5926","authenticated-orcid":false,"given":"Emma M.","family":"Groarke","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2974-7701","authenticated-orcid":false,"given":"Bhavisha A.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-0999-2519","authenticated-orcid":false,"given":"Neal S.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,22]]},"reference":[{"key":"2914_CR1","doi-asserted-by":"crossref","DOI":"10.1038\/nrdp.2017.28","volume":"3","author":"A Hill","year":"2017","unstructured":"Hill A, DeZern AE, Kinoshita T, Brodsky RA. 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