Interleukin-8 blockade prevents activated endothelial cell mediated proliferation and chemoresistance of acute myeloid leukemia.

Vindhya Vijay
Regan Miller
Gau Shoua Vue
Mida Bahareh Pezeshkian
Michael Maywood
Allison M Ast
Leylah M Drusbosky
Yuri Pompeu
Alan D Salgado
Samuel D Lipten
Timothy Geddes, Beaumont Health
Ann Marie Blenc, Beaumont Health
Yubin Ge
David A Ostrov
Christopher R Cogle
Gerard J Madlambayan


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.