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

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 chemoresistance. These findings highlight specific blockade of AML cell surface CD162 as a potential novel niche-based strategy to improve the efficacy of AML therapy.

Integrated N- and O-Glycomics of Acute Myeloid Leukemia (AML) Cell Lines

“…Especially, the role of the sialyl Lewis x/a (sLe x/a ) antigen expression in AML and its direct interaction with E-selectin in the bone marrow niche is intriguing. Reported implications of this interplay include altered homing of leukemic cells as well as regulation of their cellular proliferation and quiescence, respectively [ 17 , 18 , 19 ]. In a recent report, Barbier et al showed that the interaction between sLe x/a and E-selectin is a major determinant of chemoresistance in AML [ 20 ].…”

The high-performance technology CRISPR/Cas9 improves knowledge and management of acute myeloid leukemia

“…CRISPR-Cas9 gene editing technology also helped to estabilish that P-selectin (CD162), but not CD44, is involved in E-selectin-mediated chemo-resistance in vitro. The onset of AML occurs later when DC162 is absent from the cell surface, and sensitivity to in vivo chemotherapy is higher 35 .…”

Angiogenesis in acute myeloid leukemia

“…Very recently, the membrane E-selectin receptor expressed on HSCs and responsible for induction of chemoresistance was identified [48] . E-selectin may interact with two different membrane receptors, CD44 and CD162, expressed on hematopoietic cells.…”

“…Only the silencing of both receptors abrogates the capacity of KG1a cells to bind E-selectin; however, only CD162 is critical for E-selectin-mediated chemoresistance in vitro. Importantly, CD162 expression on AML cells in vivo is a major determinant for E-selectin binding, bone marrow vascular niche retention, and leukemic progression [48] [Figure 2]. Deletion of CD162 in AML cells induces a clear increase of the sensitivity of leukemia stem cells to therapy [48] .…”

“…Importantly, CD162 expression on AML cells in vivo is a major determinant for E-selectin binding, bone marrow vascular niche retention, and leukemic progression [48] [Figure 2]. Deletion of CD162 in AML cells induces a clear increase of the sensitivity of leukemia stem cells to therapy [48] . According to these findings, it was suggested that the binding of CD162 to E-selectin represents a potential therapeutic target to improve therapeutic outcomes through a potentiation of the efficacy of antileukemic chemotherapy.…”