Daniela S. Krause, Katherine Lazarides, Juliana B. Lewis, Ulrich H. von Andrian, and Richard A. Van Etten
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.