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Progression from chronic-phase MPN to secondary acute myeloid leukemia (sAML) is a severe complication that dramatically worsens disease prognosis. While progression to sAML is classically linked to MPN clones acquiring additional mutations, the absence of\n                  <jats:italic>JAK2<\/jats:italic>\n                  <jats:sup>V617F<\/jats:sup>\n                  in some cases of post-MPN sAML cases suggests alternative mechanisms of transformation. Utilizing patient samples and\n                  <jats:italic>in vivo<\/jats:italic>\n                  modeling, we establish that leukemic clones can emerge independently of\n                  <jats:italic>JAK2<\/jats:italic>\n                  -mutant cells and undergo positive selection in the pro-inflammatory MPN environment, leading to parallel disease evolution. Genetic and pharmacological inhibition of IL-12 and TNF\u03b1 mitigates this competitive advantage. Our data establish a new paradigm and show that disease progression in MPN can arise from parallel acute myeloid leukemia (pAML) clones.\n                <\/jats:p>","DOI":"10.1101\/2025.09.23.678057","type":"posted-content","created":{"date-parts":[[2025,9,26]],"date-time":"2025-09-26T03:10:20Z","timestamp":1758856220000},"source":"Crossref","is-referenced-by-count":0,"title":["<i>JAK2<\/i>\n                  <sup>V617F<\/sup>\n                  Myeloproliferative Neoplasms Support Parallel Evolution of Independent Leukemic Clones"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0277-1557","authenticated-orcid":false,"given":"Tyler M.","family":"Parsons","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aishwarya","family":"Krishnan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Infencia Xavier","family":"Raj","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"O\u2019Leary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Arand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maggie","family":"Cox","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen T.","family":"Oh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4669-8814","authenticated-orcid":false,"given":"Grant A.","family":"Challen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025092904151028000_2025.09.23.678057v1.1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa051113"},{"key":"2025092904151028000_2025.09.23.678057v1.2","doi-asserted-by":"crossref","first-page":"1054","DOI":"10.1016\/S0140-6736(05)71142-9","article-title":"Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders","volume":"365","year":"2005","journal-title":"The Lancet"},{"key":"2025092904151028000_2025.09.23.678057v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2005.03.023"},{"key":"2025092904151028000_2025.09.23.678057v1.4","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-12-327593"},{"key":"2025092904151028000_2025.09.23.678057v1.5","doi-asserted-by":"crossref","unstructured":"A. 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