{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:03:37Z","timestamp":1790690617969,"version":"4.1.0"},"reference-count":0,"publisher":"American Society of Hematology","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"abstract":"<jats:p>Myeloproliferative neoplasms (MPNs) arise following the acquisition of a mutation in a hematopoietic stem cell (HSC) that causes oncogenic cytokine receptor signaling. Mutations in the calreticulin (CALR) gene are the second most common key driver mutations in MPNs, yet the identity of the disease-initiating HSCs and the mechanisms underlying their clonal expansion remain elusive. Knock-in mice bearing CALRdel52 and CALRins5 mutations recapitulate disease phenotypes, with a greater HSC amplification in CALRdel52 mice. Here, we crossed these strains with transgenic reporter mice expressing GFP under the control of the Von willebrand factor (Vwf) promoter, enabling discrimination between different HSC subsets. We show that CALR-mutated MPNs are mainly initiated from the expansion of platelet-biased, Vwf-positive HSCs, without substantially altering their lineage bias. Notably, the selective amplification of Vwf-positive CALRdel52 compared to CALRins5 HSCs is associated with increased signaling of the thrombopoietin receptor MPL and activation of the integrated stress response as evidenced by eIF2a phosphorylation downstream of PERK kinase triggered by endoplasmic reticulum stress. This pathway is also transcriptionally upregulated in CALRdel52-like compared with CALRins5-like patient hematopoietic stem and progenitor cells (HSPCs), as supported by reanalysis of a previous dataset, and is associated with increased phosphorylation of eIF2a. Pharmacological inhibition of PERK markedly reduces the proliferation of mouse CALRdel52 HSCs and impairs the megakaryocytic differentiation of CALRdel52-like HSPCs from patients while sparing cells from healthy donors. These findings identify the PERK\/eIF2a pathway as a mechanistic vulnerability in the MPN cell-of-origin and offer a rationale for exploring new treatment approaches.<\/jats:p>","DOI":"10.1182\/blood.2026033236","type":"journal-article","created":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T17:03:31Z","timestamp":1790355811000},"update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":0,"title":["Characterization of disease-initiating hematopoietic stem cells in calreticulin-mutated myeloproliferative neoplasms"],"prefix":"10.1182","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7119-9326","authenticated-orcid":false,"given":"Cam\u00e9lia","family":"Benlabiod","sequence":"first","affiliation":[{"name":"INSERM UMR1287, Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laetitia","family":"Borderon","sequence":"additional","affiliation":[{"name":"INSERM UMR1287, Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-6182-4054","authenticated-orcid":false,"given":"Gurvan","family":"Hermange","sequence":"additional","affiliation":[{"name":"CDS, CentraleSup\u00e9lec, Universit\u00e9 Paris-Saclay, Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3836-2889","authenticated-orcid":false,"given":"Quentin","family":"Blampey","sequence":"additional","affiliation":[{"name":"CentraleSup\u00e9lec, Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maxime","family":"Evrard","sequence":"additional","affiliation":[{"name":"INSERM UMR1287, Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7193-9144","authenticated-orcid":false,"given":"Antonio","family":"Rodriguez-Romera","sequence":"additional","affiliation":[{"name":"MRC Weatherall Institute of Molecular Medicine, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5019-0856","authenticated-orcid":false,"given":"Stephanie G.","family":"MORENO","sequence":"additional","affiliation":[{"name":"CEA Fontenay-Aux-Roses, Fontenay-aux-Roses, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6233-1946","authenticated-orcid":false,"given":"Nathalie","family":"Gault","sequence":"additional","affiliation":[{"name":"CEA Fontenay-Aux-Roses, Fontenay-aux-Roses, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Rameau","sequence":"additional","affiliation":[{"name":"UMS AMMICa- Plate-forme Imagerie et Cytom\u00e9tries Gustave Roussy Cancer Campus, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Catelain","sequence":"additional","affiliation":[{"name":"Plateforme d'Imagerie et Cytom\u00e9trie, Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elodie","family":"Rosa","sequence":"additional","affiliation":[{"name":"INSERM UMR 1287, Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3751-393X","authenticated-orcid":false,"given":"Guillemette","family":"Fouquet","sequence":"additional","affiliation":[{"name":"Centre Hospitalier Sud Francilien, Universit\u00e9 Paris Saclay, Corbeil Essonnes, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lionel","family":"Faivre","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Th\u00e9rapie Cellulaire, H\u00f4pital Saint-Louis, AP-HP, Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1432-5300","authenticated-orcid":false,"given":"Florence","family":"Pasquier","sequence":"additional","affiliation":[{"name":"Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8198-9663","authenticated-orcid":false,"given":"Bethan","family":"Psaila","sequence":"additional","affiliation":[{"name":"MRC Weatherall Institute of Molecular Medicine, Oxford, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claus","family":"Nerlov","sequence":"additional","affiliation":[{"name":"University of Oxford, Headington, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sten Eirik W.","family":"Jacobsen","sequence":"additional","affiliation":[{"name":"Karolinska Institutet, Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4705-202X","authenticated-orcid":false,"given":"William","family":"Vainchenker","sequence":"additional","affiliation":[{"name":"Institut Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8846-5299","authenticated-orcid":false,"given":"Hana","family":"Raslova","sequence":"additional","affiliation":[{"name":"INSERM, Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7679-6197","authenticated-orcid":false,"given":"Paul-Henry","family":"Courn\u00e8de","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, CentraleSup\u00e9lec, Gif-sur-Yvette, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5915-6910","authenticated-orcid":false,"given":"Isabelle","family":"Plo","sequence":"additional","affiliation":[{"name":"INSERM U1287, Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4350-2302","authenticated-orcid":false,"given":"Caroline","family":"Marty","sequence":"additional","affiliation":[{"name":"INSERM UMR1287, Gustave Roussy, Villejuif, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2026,9,25]]},"container-title":["Blood Journal"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026033236\/2591826\/blood.2026033236.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/blood\/article-pdf\/doi\/10.1182\/blood.2026033236\/2591826\/blood.2026033236.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T13:12:12Z","timestamp":1790687532000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/doi\/10.1182\/blood.2026033236\/571230\/Characterization-of-disease-initiating"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,25]]},"references-count":0,"URL":"https:\/\/doi.org\/10.1182\/blood.2026033236","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,25]]},"article-number":"blood.2026033236"}}