CD7 drives chemoresistance in acute myeloid leukemia via cytokine-dependent NF-κB signaling

Abstract Background Aberrant expression of the lymphoid antigen CD7 is observed in acute myeloid leukemia (AML) and correlates with adverse clinical outcomes. However, its biological role and mechanistic contribution to treatment failure remain unclear. Here, we systematically characterized CD7 expression across AML subtypes and differentiation states, and investigated its impact on leukemic cell and drug resistance. Methods Integrative analysis of Mass cytometry single-cell proteomics data and public transcriptomic datasets was performed to characterize CD7 + AML. Cell lines with distinct CD7 expression levels were established for functional perturbation studies. Western blotting and immunofluorescence were performed to assess the expression of key proteins. RNA sequencing revealed the regulatory mechanisms of the associated pathways. Results CD7 expression was found in most AML subgroups at highly heterogeneous expression levels and enriched in early-stage myeloid cells. Functional perturbation studies demonstrated that CD7 supports leukemic cell fitness by promoting proliferation and cell-cycle progression while suppressing differentiation. Notably, CD7 expression conferred resistance to cytarabine and daunorubicin. Mechanistically, CD7⁺ AML cells exhibited enhanced NF-κB activation, which drove transcriptional upregulation of P-glycoprotein 1 (PGP-1) and sustained expression of the anti-apoptotic factor XIAP, thereby promoting drug efflux and apoptosis evasion. Furthermore, inflammatory cytokines, including IL-1β and TNF-α, selectively amplify NF-κB activation in a CD7-dependent manner, indicating that CD7 enables leukemic cells to exploit cytokine-rich microenvironments for survival. Conclusions Our findings identify CD7 as an active driver of chemoresistance in AML through cytokine-responsive NF-κB signaling, and highlight CD7-associated pathways as potential therapeutic vulnerabilities in CD7⁺ AML.