Selectins and their ligands are required for homing and engraftment of BCR-ABL1+ leukemic stem cells in the bone marrow niche

DS Krause, K Lazarides, JB Lewis… - Blood, The Journal …, 2014 - ashpublications.org
DS Krause, K Lazarides, JB Lewis, UH von Andrian, RA Van Etten
Blood, The Journal of the American Society of Hematology, 2014ashpublications.org
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 …
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.
ashpublications.org