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This review argues that context\u2010dependent chromatin states, not merely genetic lesions, determine disease trajectory, fibrotic transformation, and leukemic progression. We synthesize recent evidence indicating that PRC2 deficiency is supported by the strongest MPN\u2010specific evidence for BRD4 dependency, whereas PARP\/BCL\u20102 vulnerabilities associated with TET2\/IDH mutations and USP7 dependency associated with ASXL1 remain supported primarily by related myeloid malignancies or preclinical studies. Introducing the concept of an \u201cepigenetic clock\u201d of clonal evolution, we propose that MPN cells acquire progressively pathological chromatin states that can be quantified through composite methylation and accessibility scores. Importantly, temporal synthetic lethality, using short epigenetic pulses to remodel chromatin before applying targeted agents, offers a rational scheduling strategy to expose non\u2010redundant dependencies while sparing normal hematopoiesis. We outline a translational roadmap incorporating cfDNA methylome biomarkers, ongoing BET inhibitor trials, and emerging single\u2010cell perturbation approaches. Finally, we highlight the \u201cdark epigenome\u201d of repetitive elements as an unexplored therapeutic frontier. Collectively, these findings suggest that context\u2010restricted chromatin vulnerabilities may offer therapeutic opportunities for disease\u2010modifying intervention in progression\u2010prone MPN clones.<\/jats:p>","DOI":"10.1002\/hon.70239","type":"journal-article","created":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T09:07:36Z","timestamp":1787303256000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenetic Rewiring and Context\u2010Dependent Therapeutic Vulnerabilities in Myeloproliferative Neoplasms"],"prefix":"10.1002","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5481-5617","authenticated-orcid":false,"given":"Amr Ali Mohamed","family":"Abdelgawwad El\u2010Sehrawy","sequence":"first","affiliation":[{"name":"Internal Medicine, Diabetes, Endocrinology and Metabolism Mansoura University  Mansoura 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