CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia

• Published in: Haematologica (Roma) Vol. 109; no. 9; pp. 2833 - 2845
• Main Authors: Zhang, Chi, Chan, Kathy Yuen Yee, Ng, Wing Hei, Cheung, John Tak Kit, Sun, Qiwei, Wang, Han, Chung, Po Yee, Cheng, Frankie Wai Tsoi, Leung, Alex Wing Kwan, Zhang, Xiao-Bing, Lee, Po Yi, Fok, Siu Ping, Lin, Guanglan, Poon, Ellen Ngar Yun, Feng, Jian-Hua, Tang, Yan-Lai, Luo, Xue-Qun, Huang, Li-Bin, Kang, Wei, Tang, Patrick Ming Kuen, Huang, Junbin, Chen, Chun, Dong, Junchao, Mejstrikova, Ester, Cai, Jiaoyang, Liu, Yu, Shen, Shuhong, Yang, Jun J, Yuen, Patrick Man Pan, Li, Chi Kong, Leung, Kam Tong
• Format: Journal Article
• Language: English
• Published: Italy Fondazione Ferrata Storti 01.09.2024; Ferrata Storti Foundation
• Subjects: Acute Lymphoblastic Leukemia; Animals; Cell Line, Tumor; Child; Child, Preschool; Dexamethasone - pharmacology; Drug Resistance, Neoplasm - genetics; Female; Glucocorticoids - pharmacology; Glucocorticoids - therapeutic use; Humans; Male; Mice; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - metabolism; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Tetraspanin 29 - genetics; Tetraspanin 29 - metabolism
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2023.282952

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.