A transcriptional signal associated with mesenchymal stromal cells predicts overall survival in B cell acute lymphoblastic leukemia

Abstract The bone marrow microenvironment influences leukemic behavior in B-cell acute lymphoblastic leukemia (B-ALL), but clinically relevant MSC-associated transcriptional signals remain poorly defined. We derived a lineage-specific mesenchymal stromal cell (MSC) signature from a normal bone marrow single-cell RNA-sequencing reference and evaluated it in bulk transcriptomes from 56 newly diagnosed patients with B-ALL. The 35-gene signature formed two co-expression modules. The turquoise module, but not the blue module, was associated with inferior overall survival and distinct exploratory metabolic and immune-related patterns. We then developed a 10-gene-pair model from turquoise-associated genes. The model stratified survival in the derivation cohort and retained prognostic value in the external TARGET cohort using the same cutoff. In multivariable TARGET analysis, the model remained an adverse prognostic factor after adjustment for age, white blood cell count, and day 29 minimal residual disease. Exploratory analyses also identified distinct predicted drug-sensitivity associations. These findings indicate that a single-cell-informed MSC-associated transcriptional signal can support prognostic modeling, while the cellular source of this signal requires orthogonal validation.