B cell acute lymphoblastic leukemia cells mediate RANK-RANKL-dependent bone destruction

Sujeetha A Rajakumar1,2, Eniko Papp2,3, Kathy K Lee4,5, Ildiko Grandal3, Daniele Merico6, Careesa C Liu4,7, Bedilu Allo4, Lucia Zhang4,5, Marc D Grynpas4,7, Mark D Minden2,8, Johann K Hitzler3,9, Cynthia J Guidos3,10, Jayne S Danska11,2,10

  1. Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
  2. Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  3. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
  4. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5T 3H7, Canada.
  5. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  6. Center for Applied Genomics, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
  7. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  8. Princess Margaret Cancer Center, University Health Network, Toronto, Ontario M5G 2M9, Canada.
  9. Department of Pediatrics, Division of Hematology and Oncology, Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
  10. Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
  11. Program in Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada. jayne.danska@sickkids.ca.

Abstract

Although most children survive B cell acute lymphoblastic leukemia (B-ALL), they frequently experience long-term, treatment-related health problems, including osteopenia and osteonecrosis. Because some children present with fractures at ALL diagnosis, we considered the possibility that leukemic B cells contribute directly to bone pathology. To identify potential mechanisms of B-ALL-driven bone destruction, we examined the p53 -/-; Rag2 -/-; Prkdcscid/scid triple mutant (TM) mice and p53 -/-; Prkdcscid/scid double mutant (DM) mouse models of spontaneous B-ALL. In contrast to DM animals, leukemic TM mice displayed brittle bones, and the TM leukemic cells overexpressed Rankl, encoding receptor activator of nuclear factor κB ligand. RANKL is a key regulator of osteoclast differentiation and bone loss. Transfer of TM leukemic cells into immunodeficient recipient mice caused trabecular bone loss. To determine whether human B-ALL can exert similar effects, we evaluated primary human B-ALL blasts isolated at diagnosis for RANKL expression and their impact on bone pathology after their transplantation into NOD.Prkdcscid/scidIl2rgtm1Wjl /SzJ (NSG) recipient mice. Primary B-ALL cells conferred bone destruction evident in increased multinucleated osteoclasts, trabecular bone loss, destruction of the metaphyseal growth plate, and reduction in adipocyte mass in these patient-derived xenografts (PDXs). Treating PDX mice with the RANKL antagonist recombinant osteoprotegerin-Fc (rOPG-Fc) protected the bone from B-ALL-induced destruction even under conditions of heavy tumor burden. Our data demonstrate a critical role of the RANK-RANKL axis in causing B-ALL-mediated bone pathology and provide preclinical support for RANKL-targeted therapy trials to reduce acute and long-term bone destruction in these patients.

Presented By Sujeetha Rajakumar | ORCID iD

Cancer Biology, MedicineNicholas Liao2020-09 (Sep)