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Enhancer dysregulation has emerged as a hallmark of cancers, including T-cell acute lymphoblastic leukemias (T-ALL). T-ALL are aggressive malignancies characterized by marked transcriptional heterogeneity driven by distinct stages of developmental arrest and diverse noncoding alterations. How these cancers co-opt nuclear architecture to rewire enhancer connectivity remains poorly understood. Here, we report that the LDB1 chromatin architectural complex is an essential mediator of enhancer-oncogene looping that sustains oncogenic transcriptional programs across multiple T-ALL subtypes. Integrating bulk and single-cell transcriptomic data from patients with T-ALL and healthy hematopoietic controls, we show that the LDB1-dependent regulatory circuitry defines the molecular identities of distinct T-ALL subtypes while restricting plasticity toward alternative cell states. LDB1 loss dismantles chromatin looping among cell state-defining enhancers liberating them to form promiscuous interactions with nearby genes. This enhancer rewiring stimulates expression of key metabolic genes, creating a mevalonate pathway dependency exploitable with statin treatment. Our study establishes LDB1 as a central executor of T-ALL regulatory circuitry and more broadly illustrates chromatin rewiring as a source of targetable dependencies in cancer.<\/jats:p>","DOI":"10.64898\/2026.06.29.733236","type":"posted-content","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T10:58:33Z","timestamp":1782817113000},"source":"Crossref","is-referenced-by-count":0,"title":["LDB1-dependent enhancer connectivity defines T-cell leukemia identities and masks metabolic vulnerabilities"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3616-7393","authenticated-orcid":false,"given":"Rahul S","family":"Bhansali","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, Department of Medicine, Hospital of the University of Pennsylvania (Philadelphia, PA, USA)"},{"name":"Division of Hematology, The Children\u2019s Hospital of Philadelphia (Philadelphia, PA, 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