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.
Highlights
Adhesion molecules, chemokines, and cytokines sequentially regulate leukocyte migration into inflamed tissues and hematopoietic stem cell (HSC) trafficking and homing into bone marrow (BM) [1,2].By interacting with their ligands, endothelial selectins play a central role in cancer cell metastasis [3,4], immunity [5], hemostasis [6] and leukemia stem cell (LSC) interactions with the vascular niche [7,8,9].Selectins promote leukocyte recruitment on inflamed vascular endothelium by supporting leukocyte tethering and rolling [10]
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
In order to delineate the role of putative selectin ligands in blast cells, the expression of P-selectin glycoprotein ligand-1 (PSGL-1), L-selectin, CD43, CD44, sialyl Lex (sLex), Lex and cutaneous lymphocyte antigen (CLA) was assessed at the surface of myeloblasts and lymphoblasts obtained from 8 to 96 patients with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) (Figure 1 and Tables S1 and S2)
Summary
Chemokines, and cytokines sequentially regulate leukocyte migration into inflamed tissues and hematopoietic stem cell (HSC) trafficking and homing into bone marrow (BM) [1,2].By interacting with their ligands, endothelial selectins play a central role in cancer cell metastasis [3,4], immunity [5], hemostasis [6] and leukemia stem cell (LSC) interactions with the vascular niche [7,8,9].Selectins promote leukocyte recruitment on inflamed vascular endothelium by supporting leukocyte tethering and rolling [10]. Chemokines, and cytokines sequentially regulate leukocyte migration into inflamed tissues and hematopoietic stem cell (HSC) trafficking and homing into bone marrow (BM) [1,2]. By interacting with their ligands, endothelial selectins play a central role in cancer cell metastasis [3,4], immunity [5], hemostasis [6] and leukemia stem cell (LSC) interactions with the vascular niche [7,8,9]. During rolling endothelial selectins activate β2-integrins leading to leukocyte slow rolling on intercellular adhesion molecule 1 (ICAM-1) [11,12]. E-selectin is constitutively expressed on endothelial cells in BM and controls HSC homing and engraftment [2], as well as proliferation and resistance to chemotherapy [13]
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