Resistance to glucocorticoids (GC), the common agents for remission induction in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL), poses a significant therapeutic hurdle. Therefore, dissecting the mechanisms shaping GC resistance could lead to new treatment modalities. Here, we showed that CD9- BCP-ALL cells were preferentially resistant to prednisone and dexamethasone over other standard cytotoxic agents. Concordantly, we identified significantly more poor responders to the prednisone prephase among BCP-ALL patients with a CD9- phenotype, especially for those with adverse presenting features including older age, higher white cell count and BCR-ABL1. Furthermore, gain- and loss-offunction experiments dictated a definitive functional linkage between CD9 expression and GC susceptibility, as demonstrated by the reversal and acquisition of relative GC resistance in CD9low and CD9high BCP-ALL cells, respectively. Despite physical binding to the GC receptor NR3C1, CD9 did not alter its expression, phosphorylation or nuclear translocation but potentiated the induction of GC-responsive genes in GC-resistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GC against CD9- than CD9+ lymphoblasts to reverse drug resistance in vitro and in vivo. Collectively, our results elucidate a previously unrecognized regulatory function of CD9 in GC sensitivity, and inform new strategies for management of children with resistant BCP-ALL.

CLIP Department of Pediatric Hematology and Oncology 2nd Faculty of Medicine Charles University and University Hospital Motol Prague Czech Republic

Department of Anatomical and Cellular Pathology The Chinese University of Hong Kong Shatin

Department of Hematology Oncology Shanghai Children's Medical Center School of Medicine Shanghai Jiao Tong University Shanghai

Department of Hematology The 1st Affiliated Hospital of Wenzhou Medical University Wenzhou

Department of Immunology Zhongshan School of Medicine Sun Yat sen University Guangzhou

Department of Paediatrics and Adolescent Medicine Hong Kong Children's Hospital Kowloon Bay

Department of Paediatrics The Chinese University of Hong Kong Shatin

Department of Paediatrics The Chinese University of Hong Kong Shatin Hong Kong; Hong Kong Hub of Paediatric Excellence The Chinese University of Hong Kong Shatin

Department of Pediatrics The 1st Affiliated Hospital Sun Yat sen University Guangzhou

Department of Pharmaceutical Sciences St Jude Children's Research Hospital Memphis TN

Division of Hematology Oncology Department of Pediatrics The Seventh Affiliated Hospital Sun Yat sen University Shenzhen

Haihe Laboratory of Cell Ecosystem Institute of Hematology and Blood Diseases Hospital Tianjin

School of Biomedical Sciences The Chinese University of Hong Kong Shatin

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