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Leveraging cellular indexing of transcriptomes and epitopes in conjunction with T cell receptor sequencing, we identified a subset of patient samples characterized by activation of inflammatory and stem gene programs. These inflammatory T-lineage samples exhibited distinct biological features compared with other T-lineage ALL samples, including the production of proinflammatory cytokines, prevalence of mutations affecting cytokine signaling and chromatin remodeling, an altered immune microenvironment, and poor treatment responses. Moreover, we found that, although inflammatory T-lineage ALL samples were less sensitive to dexamethasone, they exhibited unique sensitivity to a BCL-2 inhibitor, venetoclax. To facilitate classification of patients with T-lineage ALL, we developed a computational inflammatory gene signature scoring system, which stratified patients and was associated with disease prognosis in three additional patient cohorts. By identifying a high-risk T-lineage ALL subtype on the basis of an inflammatory score, our study provides a framework for targeted therapeutic approaches for these challenging-to-treat cancers.<\/jats:p>","DOI":"10.1126\/scitranslmed.adr2012","type":"journal-article","created":{"date-parts":[[2025,1,1]],"date-time":"2025-01-01T18:58:41Z","timestamp":1735757921000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":12,"title":["An inflammatory state defines a high-risk T-lineage acute lymphoblastic leukemia subgroup"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2165-0099","authenticated-orcid":true,"given":"Mark","family":"Gower","sequence":"first","affiliation":[{"name":"Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C4, 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