Acute Myeloid Leukemia Chemo-Resistance Is Mediated by E-selectin Receptor CD162 in Bone Marrow Niches.

Johanna Erbani,Ingrid G Winkler,Joshua Tay,Jean-Pierre Levesque,Valerie Barbier

doi:10.3389/fcell.2020.00668

Abstract

The interactions of leukemia cells with the bone marrow (BM) microenvironment is critical for disease progression and resistance to treatment. We have recently found that the vascular adhesion molecule E-(endothelial)-selectin is a key niche component that directly mediates acute myeloid leukemia (AML) chemo-resistance, revealing E-selectin as a promising therapeutic target. To understand how E-selectin promotes AML survival, we investigated the potential receptors on AML cells involved in E-selectin-mediated chemo-resistance. Using CRISPR-Cas9 gene editing to selectively suppress canonical E-selectin receptors CD44 or P-selectin glycoprotein ligand-1 (PSGL-1/CD162) from human AML cell line KG1a, we show that CD162, but not CD44, is necessary for E-selectin-mediated chemo-resistance in vitro. Using preclinical models of murine AML, we then demonstrate that absence of CD162 on AML cell surface leads to a significant delay in the onset of leukemia and a significant increase in sensitivity to chemotherapy in vivo associated with a more rapid in vivo proliferation compared to wild-type AML and a lower BM retention. Together, these data reveal for the first time that CD162 is a key AML cell surface receptor involved in AML progression, BM retention and chemo-resistance. These findings highlight specific blockade of AML cell surface CD162 as a potential novel niche-based strategy to improve the efficacy of AML therapy.

Highlights

Acute myeloid leukemia (AML) is an aggressive hematological cancer, where immature myeloid blasts accumulate within the bone marrow (BM) and perturb normal hematopoiesis (DiNardo and Cortes, 2016)
Together these data suggest that AML cell adhesion to E-selectin may trigger a strong polarization or clustering of CD162 toward the E-selectin-IgM binding site, which was not observed with CD44
This study explores the mechanisms by which vascular E-selectinmediated adhesion promotes chemo-resistance in AML and investigate canonical cell surface receptors potentially involved

Summary

Introduction

Acute myeloid leukemia (AML) is an aggressive hematological cancer, where immature myeloid blasts accumulate within the bone marrow (BM) and perturb normal hematopoiesis (DiNardo and Cortes, 2016). Using mice knocked-out for the E-selectin gene and a therapeutically relevant E-selectin antagonist (GMI1271/Uproleselan), we have recently discovered that E-selectin regulates malignant AML cells by influencing therapy response. The absence or blockade of E-selectin at the vascular niche sensitizes AML blasts to chemotherapy and significantly extends disease-free survival duration in treated leukemic mice (Barbier et al, 2020). These findings highlight endothelial E-selectin as a promising therapeutic target, and are the basis for two phase III clinical trials to test the activity of GMI1271 in combination with chemotherapy in adult AML patients (NCT03616470, NCT03701308)

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