Interleukin-8 blockade prevents activated endothelial cell mediated proliferation and chemoresistance of acute myeloid leukemia.
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.
Vijay V, Miller R, Vue GS, Pezeshkian MB, Maywood M, Ast AM, Drusbosky LM, Pompeu Y, Salgado AD, Lipten SD, Geddes T, Blenc AM, Ge Y, Ostrov DA, Cogle CR, Madlambayan GJ. Interleukin-8 blockade prevents activated endothelial cell mediated proliferation and chemoresistance of acute myeloid leukemia. Leuk Res. 2019 Sep;84:106180. doi: 10.1016/j.leukres.2019.106180. Epub 2019 Jul 3. PMID: 31299413; PMCID: PMC6857733.