CD9 shapes glucocorticoid sensitivity in pediatric B-cell precursor acute lymphoblastic leukemia.
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Officially Accepted for Publication
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AbstractResistance to glucocorticoids (GCs), 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-of-function 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 GCresistant cells. Importantly, the MEK inhibitor trametinib exhibited higher synergy with GCs 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.
Acceptance Date22/03/2024
All Author(s) ListZhang C, Chan KYY, Ng WH, Cheung JTK, Sun Q, Wang H, Chung PY, Cheng FWT, Leung AWK, Zhang XB, Lee PY, Fok SP, Lin G, Poon ENY, Feng JH, Tang YL, Luo XQ, Huang LB, Kang W, Tang PMK, Huang J, Chen C, Dong J, Mejstrikova E, Cai J, Liu Y, Shen S, Yang JJ, Yuen PMP, Li CK, Leung KT
Journal nameHaematologica
Year2024
PublisherFerrata Storti Foundation, Pavia, Italy
Article number38572553
ISSN0390-6078
LanguagesEnglish-United Kingdom
