An inflammatory state defines a high-risk T-lineage acute lymphoblastic leukemia subgroup [CITE-seq]

T-cell acute lymphoblastic leukemia (T-ALL), a malignant neoplasm of immature T cells, is a particularly aggressive leukemia with diverse subtypes and limited therapeutic options. Recent studies showed that the responsiveness of drugs in preclinical models of T-ALL is linked to the specific biological characteristics exhibited by the T-ALL subtype. In order to comprehensively explore the underlying heterogeneity of T-ALL, we performed an integrative analysis of bone marrow biopsies from newly diagnosed T-ALL patients. Leveraging a combination of cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) along with T-cell receptor sequencing (TCR-seq), we obtained a comprehensive molecular characterization of T-ALL. Our analysis uncovered a distinct subset of inflammatory T-ALLs (iT-ALLs) resembling early T-cell precursor (ETP) leukemias, characterized by enriched expression of hematopoietic stem and progenitor signatures, inflammatory gene programs, and poor survival outcomes. Furthermore, our investigation revealed a significant association between the transcription factor interferon regulatory factor 5 (IRF5) activity and the iT-ALL subgroup. Utilizing an IRF5 scoring system, we demonstrated its potential as a robust biomarker for classifying T-ALL patients and predicting disease prognosis. Our work provides a framework for identifying high-risk T-ALL patients based on the IRF5 activity and a rational for considering the inflammatory state in tailoring therapeutic interventions.