Targeting Leukemic Stem Cells: The Synergistic Effect of GMI-1359 in FLT3-ITD AML Therapy

The abnormal function of FMS-like tyrosine kinase-3 (FLT3), often due to internal tandem duplication (ITD) mutations, is a frequent occurrence in individuals with acute myeloid leukemia (AML), making FLT3 a promising target for treatment. FLT3 inhibitors like sorafenib have shown positive results in reducing the number of leukemia cells in the blood of patients with FLT3 mutations. However, these treatments are less effective against leukemic stem cells within the bone marrow (BM) environment. The BM contains cytokines and molecules such as CXCR4 and E-selectin, which may shield AML cells from chemotherapy. Sorafenib treatment has been noted to increase CXCR4 levels in mutated cells. Leukemia cells can also activate endothelial cells, leading to the adhesion of some leukemia cells through E-selectin, which can protect them from chemotherapy.

In a recent study, researchers examined the efficacy of GMI-1359, a dual antagonist of CXCR4 and E-selectin, against FLT3-ITD-mutant AML both in vitro and in vivo. The study found that several AML cell lines exhibited high levels of CXCR4 expression, which increased under hypoxic conditions similar to those in the BM. FLT3-ITD leukemic cell lines also showed increased expression of hypoxia-responsive E-selectin ligands, such as CD44, under hypoxic conditions. The presence of GMI-1359 in co-cultures of FLT3-ITD-mutant leukemia cells with mesenchymal stem cells and endothelial cells significantly reduced leukemic cell adhesion. GMI-1359 was also found to counteract the protective effects of the BM environment, leading to increased apoptosis in leukemic cells treated with sorafenib.

In vivo studies using female SCID beige mice demonstrated that a combination of GMI-1359 and standard chemotherapy resulted in a significant survival advantage over controls or chemotherapy alone. The single administration of GMI-1359 was found to increase circulating white blood cells and leukemic cells, suggesting that it may disrupt the protective tumor microenvironment and mobilize cells from the BM niche. These results support the further evaluation of GMI-1359 in patients with FLT3-mutant AML.