Epigenetic Rewiring and Context‐Dependent Therapeutic Vulnerabilities in Myeloproliferative Neoplasms

Myeloproliferative neoplasms (MPN) are shaped by epigenetic rewiring that extends beyond canonical JAK2V617F-driven signaling. This review argues that context-dependent 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-specific evidence for BRD4 dependency, whereas PARP/BCL-2 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 "epigenetic clock" 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-redundant dependencies while sparing normal hematopoiesis. We outline a translational roadmap incorporating cfDNA methylome biomarkers, ongoing BET inhibitor trials, and emerging single-cell perturbation approaches. Finally, we highlight the "dark epigenome" of repetitive elements as an unexplored therapeutic frontier. Collectively, these findings suggest that context-restricted chromatin vulnerabilities may offer therapeutic opportunities for disease-modifying intervention in progression-prone MPN clones.

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