FLT3 inhibitors upregulate CXCR4 and E-selectin ligands through suppression of ERK in AML and combined inhibition of CXCR4/E-selectin enhances anti-leukemia efficacy of FLT3-targeted therapy

Abstract

CXC chemokine receptor 4 (CXCR4)/CXC motif ligand 12 (CXCL12) and E-(endothelial)-selectin/E-selectin ligands (E-selectin-L) axes play critical roles in leukemia cell homing to the bone marrow niche and are closely associated with resistance to FLT3-targeted therapy in FLT3-mutant acute myeloid leukemia (AML) patients. Hence, it is imperative to co-target CXCR4/E-selectin/FLT3 in FLT3 mutant AML. Herein, we determined whether FLT3 inhibition modulates CXCR4/E-selectin-L levels and whether co-targeting CXCR4/E-selectin enhances the anti-leukemia effects and reduces bone marrow niche-mediated resistance in FLT3-targeted therapy. Our results demonstrate that CXCR4/E-selectin-L are transcriptionally upregulated by FLT3 inhibition. Concomitant blockage of CXCR4/E-selectin with the dual inhibitor GMI-1359 disrupts leukemia cell homing and migration to bone marrow niches. Combination treatment with GMI-1359 and quizartinib significantly reduced leukemia cell burden and extended mouse survival in a patient derived xenograft AML mouse model. These findings provide pre-clinical rationale for combined CXCR4/E-selectin/FLT3 targeting in FLT3-mutant AML.

Targeting hematologic malignancies by inhibiting E-selectin: A sweet spot for AML therapy?

“…Another E-selectin inhibitor, GMI-1359, inhibits CXCR4 in addition to E-selectin. Both CXCR4 and E-selectin ligand are upregulated in FLT3-ITD mutated AML patient blasts, and GMI-1359 with quizartinib treatment improved survival of immunodeficient NSG mice implanted with FLT3-ITD mutated AML [ 115 ]. These pre-clinical experiments provide rationale for additional testing of GMI-1359 in treatment of FLT3-ITD mutated AML.…”

The interplay of FLT3 and CXCR4 in acute myeloid leukemia: an ongoing debate

“…A recently published study by Jia et al. suggests that FLT3-ITD signaling could inhibit CXCR4 expression as it reports that treatment of FLT3-ITD expressing MOLM-14 cells with a FLT3 inhibitor resulted in an upregulation of CXCR4 on the cell surface, as well as on the mRNA level ( 35 ). If this mechanism proves true, the CXCR4 surface expression would increase during FLT3 inhibitor treatment, which might then lead to enhanced residing of the AML cells in the BMM.…”