1. Shanghai Institute of Hematology, State Key Laboratory of Medical Genomics, National Research Center for Translational Medicine (Shanghai), Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
2. School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China
Corresponding author:
mengzhe01@sjtu.edu.cn
lhm01n80@rjh.com.cn
ty12260@rjh.com.cn
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History+
Received
Accepted
Published Online
2026-04-19
2026-07-20
2026-10-30
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Abstract
Heterochromatin has long been viewed as a static, transcriptionally inert component of the genome. However, emerging evidence redefines it as a dynamic, highly organized regulatory scaffold that integrates epigenetic modifications, higher-order chromatin architecture, and phase-separation mechanisms to control cell identity. In the hematopoietic system, these heterochromatin-dependent spatiotemporal processes are essential for stabilizing lineage-specific transcriptional programs and preserving cellular memory. Importantly, recent studies suggest that disruption of heterochromatin is not merely a consequence of malignant transformation but may also drive hematopoietic aging and leukemogenesis. Alterations in key heterochromatin regulators, aberrant redistribution of H3K9me3 and H3K27me3 marks, and rewiring of heterochromatin domains can reshape transcriptional landscapes, dysregulate stem-like states, and facilitate immune evasion. Here, we propose that heterochromatin functions as a central organizational hub linking epigenetic regulation to three-dimensional genome architecture in hematologic malignancies. We discuss emerging mechanisms governing heterochromatin assembly, maintenance, and plasticity, and highlight unresolved questions regarding its reversibility and targetability. Finally, we examine therapeutic strategies to modulate heterochromatin and argue that targeting heterochromatin architecture is a promising yet underexplored avenue for cancer treatment.
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