髓系白血病
癌症研究
阿糖胞苷
白血病
细胞生长
免疫学
医学
化学
生物化学
作者
Vindhya Vijay,Regan Miller,Gau Shoua Vue,Mida Bahareh Pezeshkian,Michael J. Maywood,Allison Ast,Leylah Drusbosky,Y.A. Pompeu,Alan D. Salgado,Samuel D. Lipten,Timothy J. Geddes,Ann Marie Blenc,Yubin Ge,David A. Ostrov,Christopher R. Cogle,Gerard J. Madlambayan
标识
DOI:10.1016/j.leukres.2019.106180
摘要
One of the greatest challenges in treating acute myeloid leukemia (AML) is chemotherapy refractory disease. Previously, we demonstrated a novel mechanism whereby AML-induced endothelial cell (EC) activation leads to subsequent leukemia cell adherence, quiescence and chemoresistance, identifying activated ECs as potential mediators of relapse. We now show mechanistically that EC activation induces the secretion of interleukin-8 (IL-8) leading to significant expansion of non-adherent AML cells and resistance to cytarabine (Ara-C). Through crystallography and computational modeling, we identified a pocket within IL-8 responsible for receptor binding, screened for small molecules that fit within this pocket, and blocked IL-8 induced proliferation and chemo-protection of AML cells with a hit compound. Results from this study show a new therapeutic strategy for targeting the sanctuary of an activated leukemia microenvironment.
科研通智能强力驱动
Strongly Powered by AbleSci AI