Leukemic progenitors from patients with chronic myelogenous leukemia (CML) have defects in the adhesive function of β1 integrins and in their response to the chemokine CXCL12 (Stem Cells 2002;3:259), pathways that are critical for engraftment and maintenance of normal hematopoietic stem cells (HSC) in the bone marrow (BM) niche. Previous studies in a mouse BCR-ABL1 retroviral transduction/transplantation model of CML demonstrated that BCR-ABL1+ leukemic stem cells, but not normal murine HSC, are dependent on expression of the CD44 adhesion molecule for BM homing and engraftment (Nat Med 2006;12:1175). To investigate further other adhesion molecules required for stable engraftment of CML stem cells, we employed donor and recipient mice with targeted mutations in genes encoding selectins and those required for expression of selectin ligands in the mouse retroviral CML model. Neither the β1 integrin ligand VCAM-1 nor P-selectin was required in the BM endothelium of recipient mice for efficient engraftment and induction of CML-like myeloproliferative neoplasia (MPN) by BCR-ABL1-expressing stem cells. By contrast, loss of recipient E-selectin significantly impaired engraftment of BCR-ABL1+ stem/progenitor cells, as demonstrated by decreased frequency of BM proviral leukemia-initiating clones, a defect overcome by direct intrafemoral injection of the leukemic cells. We also demonstrated a requirement for expression of selectin ligands on the leukemic stem cells, as BCR-ABL1-expressing stem cells lacking enzymes contributing to biosynthesis of selectin ligands (Core2 or Fucosyltransferases IV and VII) exhibited decreased efficiency of engraftment, resulting in attenuated disease. Further, donor cells deficient in P-selectin glycoprotein ligand-1 (PSGL-1) or in both PSGL-1 and CD44, a glycoform of which can function as a selectin ligand on hematopoietic stem cells (J. Biol Chem 2001;278:47623), displayed intermediate or profound impairment in engraftment of CML-like leukemia, respectively. Removal of selectin ligands by neuraminidase treatment of BCR-ABL1-transduced HSC blocked engraftment of leukemic stem cells and resulted in long-term survival of transplant recipients. Together, these results demonstrate that BCR-ABL1-expressing stem cells are dependent on selectin ligands, expressed on PSGL-1 and possibly on CD44, and their interaction with BM E-selectin for engraftment and retention in the BM microenvironment. Disrupting these niche interactions could represent new avenues for targeting CML stem cells that are resistant to ABL kinase inhibitors like imatinib.
Van Etten:Bristol Myers Squibb: Consultancy; Deciphera Pharmaceuticals: Consultancy; TEVA Pharmaceuticals: Consultancy, Research Funding.
Asterisk with author names denotes non-ASH members.