Volume 10 Number 1 2026
Chromatin Architecture Disruption Drives Transcriptional Dysregulation and Reveals Therapeutic Vulnerabilities in Acute Myeloid Leukaemia
Gede Bagus Yoga Satriadinatha1* Reza Vaghebin 2, Khatereh Akbarimashak 3, Rasoul Pourhakimrezaei 3, Mohammad Javad Mousavi 4
Integrative Biomedical Research 10 (1) 1-8 https://doi.org/10.25163/biomedical.10110922
Submitted: 19 March 2026 Revised: 06 May 2026 Accepted: 15 May 2026 Published: 17 May 2026
Acute myeloid leukaemia (AML) has traditionally been framed as a disease of sequential somatic mutations, yet this account has never fully explained why genetically similar clones behave so differently at the bedside. A growing body of work — still, it must be said, somewhat scattered across disciplines — suggests that the missing piece lies in the physical folding of the genome itself. Loss of cohesin subunits such as STAG2, together with oncofusion proteins including PML-RARA, AML1-ETO, and CBFb-SMMHC, appear to reorganise three-dimensional (3D) chromatin loops, enhancer-promoter contacts, and topologically associating domains (TADs) in ways that lock myeloid precursors into a self-renewing, undifferentiated state. We conducted a structured narrative synthesis of the mechanistic and translational literature on chromatin topology in AML, following a reproducible, search and eligibility framework applied to primary experimental studies, mechanistic reviews, and early-phase clinical reports published through mid-2026. Evidence was organised into four interacting conceptual nodes — epigenetic/metabolic remodelling, 3D genomic architecture, epitranscriptomic regulation, and clinical translation — and cross-referenced against four synthesis tables covering molecular subtypes, epigenetic regulators, topological alterations, and therapeutics. Across the synthesised literature, STAG2-deficient cohesin selectively erodes short-range (<500 kb) enhancer-promoter loops without being rescued by the paralog STAG1, while PML-RARA and CBFb-SMMHC independently collapse or repurpose loop networks anchored on MYC and myeloid differentiation genes. Epitranscriptomic control by METTL3/METTL14 and YTHDF2 reinforces this topological block at the level of mRNA stability and translation, and menin-KMT2A inhibitors such as revumenib and ziftomenib translate this understanding into clinically meaningful, if resistance-prone, responses. Taken together, the evidence points toward AML being less a catalogue of isolated lesions and more a disease of disrupted spatial genome logic — one in which epigenetic, topological, and epitranscriptomic layers converge on a shared, and importantly reversible, differentiation block. This reframing carries direct implications for how risk is stratified and how combination therapy is sequenced.
Keywords: acute myeloid leukaemia; chromatin architecture; cohesin/STAG2; oncofusion proteins; epitranscriptomics; enhancer-promoter looping; menin inhibitors
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