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We developed an artificial intelligence (AI) framework with human interpretability to distinguish prePMF from ET using digitized hematoxylin and eosin-stained bone marrow biopsy (BMB) slides. Trained on an initial cohort of MPN patients with thrombocytosis, the AI model achieved an AUROC of 0.89 and accuracy of 92.3%. To assess the image features guiding predictions, we generated synthetic images which potentially exaggerate disease-specific morphologies. In a blinded survey, hematopathologists reviewed both real and AI-generated images. While human experts frequently agreed with AI predictions on diagnosis with real images, diagnostic discordance reached up to 88% for AI-generated ET images despite being correctly predicted by AI. We further quantified marrow cellularity and adiposity in the real and generated images, which revealed a higher proportion of fat content in all ET images (42.0%) compared to prePMF (28.9%). These findings suggest that AI can utilize morphological cues distinct from current established diagnostic criteria, such as proportion of adiposity to distinguish types of MPNs. Thus, an AI-assisted diagnostic tool underscores the potential of AI to augment histopathologic evaluation and allow identification of more specific subpopulations of forms of MPNs.<\/jats:p>","DOI":"10.1038\/s41375-026-02893-7","type":"journal-article","created":{"date-parts":[[2026,2,20]],"date-time":"2026-02-20T12:34:27Z","timestamp":1771590867000},"page":"1018-1026","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Artificial intelligence differentiates prefibrotic primary myelofibrosis with thrombocytosis from essential thrombocythemia using digitized bone marrow biopsy images"],"prefix":"10.1038","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8736-8726","authenticated-orcid":false,"given":"Andrew","family":"Srisuwananukorn","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6241-1206","authenticated-orcid":false,"given":"Giuseppe Gaetano","family":"Loscocco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James M.","family":"Dolezal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew T.","family":"Kuykendall","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-5317-7533","authenticated-orcid":false,"given":"Raffaella","family":"Santi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Avani M.","family":"Singh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1809-284X","authenticated-orcid":false,"given":"Paola","family":"Guglielmelli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5755-0730","authenticated-orcid":false,"given":"Alessandro Maria","family":"Vannucchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed E.","family":"Salama","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander T.","family":"Pearson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6564-6732","authenticated-orcid":false,"given":"Ronald","family":"Hoffman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,2,20]]},"reference":[{"key":"2893_CR1","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1038\/sj.leu.2404914","volume":"22","author":"G Barosi","year":"2008","unstructured":"Barosi G, Mesa RA, Thiele J, Cervantes F, Campbell PJ, Verstovsek S, et al. 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