Abstract
The importance of the cell surface receptor CXCR4 and the chemokine stromal cell-derived factor-1 (SDF-1/CXCL12) is well-established in normal and malignant hematopoiesis. The Protein Epitope Mimetic POL5551 is a novel and potent antagonist of CXCR4. POL5551 efficiently mobilizes hematopoietic stem and progenitor cells, but its effects in acute lymphoblastic leukemia (ALL) have not been reported. Here, we demonstrate that POL5551 is a potent antagonist of CXCR4 in pre-B and T cell ALL cell lines and pediatric ALL primary samples. POL5551 has activity at nanomolar concentrations in decreasing CXCR4 antibody binding, blocking SDF-1α-mediated phosphorylation of ERK1/2, inhibiting SDF-1α-induced chemotaxis, and reversing stromal-mediated protection from chemotherapy. POL5551 is significantly more effective at inhibiting CXCR4 antibody binding than the FDA-approved CXCR4 inhibitor plerixafor in ALL cell lines and primary samples. We also show that treatment with POL5551 in vitro and cytarabine +/- POL5551 in vivo modulates surface expression of adhesion molecules, findings that may guide the optimal clinical use of POL5551. Finally, we demonstrate that POL5551 increases sensitivity to cytarabine in a xenograft model of a high-risk pediatric ALL, infant MLL-rearranged (MLL-R) ALL. Therefore, disruption of the CXCR4/SDF-1 axis with POL5551 may improve outcomes in children with high-risk ALL.
Highlights
acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy
We previously demonstrated that CXCR4 is an important mediator of chemotherapy resistance in pediatric ALL and acute myeloid leukemia (AML), and that treatment with the FDA-approved CXCR4 inhibitor plerixafor could reverse stromal protection and chemotherapy resistance [8,9,10]
We offer the first report of this novel CXCR4 antagonist in pediatric ALL
Summary
ALL is the most common pediatric malignancy. Advances in the treatment of ALL, including the use of multi-agent chemotherapy, improvements in supportive care, and risk stratification, have led to event-free survival rates that are approaching 90% [1]. [2] We and others have demonstrated that interaction with the bone marrow microenvironment is important in a variety of hematopoietic malignancies [3,4,5,6,7,8,9,10]. Interaction between the cell surface receptor CXCR4 and the chemokine SDF-1 (CXCL12) is critical in signaling between leukemic blasts and the bone marrow microenvironment [11,12,13,14,15,16,17]. We demonstrate that POL5551 is a potent antagonist of surface CXCR4 in pediatric ALL cell lines and primary samples. Interruption of leukemia-microenvironment signaling with POL5551 may prove to be an effective strategy in the treatment of pediatric ALL
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