GMI-1271: A Promising E-Selectin Inhibitor Targeting AML Cell Adhesion and Mobilization in Engrafted Mice

The study examines the expression of HCELL, a glycoform of CD44, in acute myeloid leukemia (AML) cells. It reveals that a high percentage of AML blasts and leukemia stem cells (LSCs) express CD44, with a significantly higher mean fluorescence intensity compared to other adhesion receptors. The research confirms that a majority of AML blasts express an E-selectin ligand, identified as HCELL through immunoprecipitation and staining with HECA 452 antibody. This antibody not only recognizes the HCELL but also the human lymphocyte homing receptor CLA. The study finds that HECA 452 labels AML blasts and LSCs, with LSCs showing a higher expression in most cases. Additionally, HECA 452 labels 94% of AML cells in NODscid IL2Rgc^null^ mice, indicating that HCELL may be enriched on LSCs. The research also shows morphological changes in AML blasts upon binding to E-selectin-coated surfaces and their interaction with endothelial cells. The E-selectin-specific inhibitor GMI-1271 reduces the adhesion of AML cells to E-selectin without inducing chemotherapy resistance. Furthermore, a dual inhibitor of E-selectin and CXCR4, GMI-1215, is found to be more effective in mobilizing human AML in mice than the CXCR4 inhibitor alone. The study concludes with the observation that GMI-1271, at a specific dosage, increases the mobilization of both human and murine cells in mice with human AML. Initial experiments combining GMI-1271 with daunorubicin and cytarabine show a greater depletion of AML cells from bone marrow and spleen. The research suggests that the interaction between HCELL and E-selectin could be a potential therapeutic target for AML.