title: Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche.
abstract: We investigated adhesion pathways that contribute to engraftment of breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL1)-induced chronic myelogenous leukemia (CML)-like myeloproliferative neoplasia in a mouse retroviral transduction/transplantation model. Compared with normal stem/progenitor cells, BCR-ABL1(+) progenitors had similar expression of very late antigen-4 (VLA4), VLA5, leukocyte functional antigen-1, and CXCR4 but lower expression of P-selectin glycoprotein ligand-1 (PSGL-1) and of L-selectin. Whereas vascular cell adhesion molecule-1 and P-selectin were not required, deficiency of E-selectin in the recipient bone marrow endothelium significantly reduced engraftment by BCR-ABL1-expressing stem cells following intravenous injection, with leukemogenesis restored by direct intrafemoral injection. BCR-ABL1-expressing cells deficient for PSGL-1 or the selectin ligand-synthesizing enzymes core-2 β1,6-N-acetylglucosaminyltransferase or fucosyltransferases IV/VII were impaired for engraftment, and destruction of selectin ligands on leukemic progenitors by neuraminidase reduced engraftment. BCR-ABL1-expressing L-selectin-deficient progenitors were also defective in homing and engraftment, with leukemogenesis rescued by coexpression of chimeric E/L-selectin. Antibody to L-selectin decreased the engraftment of BCR-ABL1-transduced stem cells. These results establish that BCR-ABL1(+) leukemic stem cells rely to a greater extent on selectins and their ligands for homing and engraftment than do normal stem cells. Selectin blockade is a novel strategy to exploit differences between normal and leukemic stem cells that may be beneficial in autologous transplantation for CML and perhaps other leukemias.
authors.affiliation: Division of Hematology/Oncology and Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA;
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Krause
authors.forename: Katherine
authors.initials: K
authors.lastname: Lazarides
authors.forename: Juliana B
authors.initials: JB
authors.lastname: Lewis
authors.forename: Ulrich H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000473:pathology*; D001854:Bone Marrow Cells / Q000473:pathology; D002465:Cell Movement / Q000235:genetics*; D002478:Cells, Cultured; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000473:pathology*; D008024:Ligands; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D019087:Selectins / Q000502:physiology*; D055153:Stem Cell Niche
chemical_list: D008024:Ligands; D019087:Selectins; D016044:Fusion Proteins, bcr-abl