Acute Myeloid and Lymphoblastic Leukemia Cell Interactions with Endothelial Selectins: Critical Role of PSGL-1, CD44 and CD43

Abstract

Acute myeloid and lymphoblastic leukemia are poor prognosis hematologic malignancies, which disseminate from the bone marrow into the blood. Blast interactions with selectins expressed by vascular endothelium promote the development of drug resistance and leukostasis. While the role of selectins in initiating leukemia blast adhesion is established, our knowledge of the involved selectin ligands is incomplete. Using various primary acute leukemia cells and U937 monoblasts, we identified here functional selectin ligands expressed by myeloblasts and lymphoblasts by performing biochemical studies, expression inhibition by RNA interference and flow adhesion assays on recombinant selectins or selectin ligands immunoadsorbed from primary blast cells. Results demonstrate that P-selectin glycoprotein ligand-1 (PSGL-1) is the major P-selectin ligand on myeloblasts, while it is much less frequently expressed and used by lymphoblasts to interact with endothelial selectins. To roll on E-selectin, myeloblasts use PSGL-1, CD44, and CD43 to various extents and the contribution of these ligands varies strongly among patients. In contrast, the interactions of PSGL-1-deficient lymphoblasts with E-selectin are mainly supported by CD43 and/or CD44. By identifying key selectin ligands expressed by acute leukemia blasts, this study offers novel insight into their involvement in mediating acute leukemia cell adhesion with vascular endothelium and may identify novel therapeutic targets.

Hyperleukocytosis and Leukostasis in Acute Myeloid Leukemia: Can a Better Understanding of the Underlying Molecular Pathophysiology Lead to Novel Treatments?

“…AML blasts have been shown to express various cell adhesion molecules such as CD11, CD49, PSGL-1, and L-selectin with significant differences between various subtypes of AML blasts [ 18 , 19 , 43 , 67 ]. Additionally, leukemic blasts—in contrast to normal neutrophils—have shown to interact with E-selectin via PSGL-1, CD43, and CD44 and to exhibit various expression and activity levels of those selectin ligands that are distinct from normal HSCs and are associated with chemotherapy resistance [ 18 , 20 ].…”

“…However, the molecular processes driving the development of hyperleukocytosis are still incompletely understood. Over the past two decades the role of adhesion molecules and cytokines in both the homing of HSCs into the bone marrow and the development of leukostasis has been increasingly characterized [ 18 ]. Especially endothelial selectins that promote adherence of leukemic blasts to the vascular endothelium have been identified as essential players not only in the development of leukostasis but also in chemotherapy resistance and leukemic stem cell (LSC) survival [ 18 , 19 , 20 , 21 ].…”

“…Over the past two decades the role of adhesion molecules and cytokines in both the homing of HSCs into the bone marrow and the development of leukostasis has been increasingly characterized [ 18 ]. Especially endothelial selectins that promote adherence of leukemic blasts to the vascular endothelium have been identified as essential players not only in the development of leukostasis but also in chemotherapy resistance and leukemic stem cell (LSC) survival [ 18 , 19 , 20 , 21 ]. Herein, we provide a brief overview of the interaction of HSCs and LSCs in the bone marrow environment under physiologic circumstances as well as in AML before shifting to the processes in the peripheral circulation leading to DIC, TLS, and leukostasis and a discussion of potential therapeutic targets.…”

Don’t sugarcoat it: How glycocalyx composition influences cancer progression

“…The glycoproteins P-selectin glycoprotein ligand-1 (PSGL-1), CD43 (leukosialin), and CD44 are components of the glycocalyx that act as regulators of cell–cell, cell–endothelial, and cell–ECM interactions in cancer (Spertini et al, 2019). PSGL-1 is a cell surface glycoprotein found on all leukocytes and some cancers that is a critical regulator of selectin binding to the endothelial surface (McEver and Cummings, 1997).…”

Glycoengineering of NK cells with glycan ligands of CD22 and selectins for B-cell lymphoma therapy

“…24 After subjecting NK-92MI and CIK cells to Because most leukemia and lymphoma cells require a close relationship with the bone marrow microenvironment for their survival and disease progression. 37,38 We reasoned that NK cells may not be sufficiently trafficking to bone marrow to attack B lymphoma where they reside in situ. The cell adhesion molecule E-selectin is constitutively expressed in the bone marrow and plays a critical role in promoting leukemia cell adhesion, survival, and resistance to chemotherapy.…”