达沙替尼
糖皮质激素受体
癌症研究
糖皮质激素
祖细胞
PI3K/AKT/mTOR通路
信号转导
生物
转录组
细胞培养
离体
细胞生物学
体内
细胞生长
干细胞
免疫学
基因表达
酪氨酸激酶
基因
生物化学
遗传学
作者
Jolanda Sarno,Pablo Domizi,Yuxuan Liu,Milton Merchant,Christina Bligaard Pedersen,Dorra Jedoui,Astraea Jager,Garry P. Nolan,Giuseppe Gaipa,Sean C. Bendall,Felice-Alessio Bava,Kara L. Davis
标识
DOI:10.1038/s41467-023-38456-y
摘要
Resistance to glucocorticoids (GC) is associated with an increased risk of relapse in B-cell progenitor acute lymphoblastic leukemia (BCP-ALL). Performing transcriptomic and single-cell proteomic studies in healthy B-cell progenitors, we herein identify coordination between the glucocorticoid receptor pathway with B-cell developmental pathways. Healthy pro-B cells most highly express the glucocorticoid receptor, and this developmental expression is conserved in primary BCP-ALL cells from patients at diagnosis and relapse. In-vitro and in vivo glucocorticoid treatment of primary BCP-ALL cells demonstrate that the interplay between B-cell development and the glucocorticoid pathways is crucial for GC resistance in leukemic cells. Gene set enrichment analysis in BCP-ALL cell lines surviving GC treatment show enrichment of B cell receptor signaling pathways. In addition, primary BCP-ALL cells surviving GC treatment in vitro and in vivo demonstrate a late pre-B cell phenotype with activation of PI3K/mTOR and CREB signaling. Dasatinib, a multi-kinase inhibitor, most effectively targets this active signaling in GC-resistant cells, and when combined with glucocorticoids, results in increased cell death in vitro and decreased leukemic burden and prolonged survival in an in vivo xenograft model. Targeting the active signaling through the addition of dasatinib may represent a therapeutic approach to overcome GC resistance in BCP-ALL.
科研通智能强力驱动
Strongly Powered by AbleSci AI