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

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.

Bad to the bone: B cell acute lymphoblastic leukemia cells mediate bone destruction

“…8 We showed that RANKL, the critical regulator of bone resorption, was abundantly expressed by the mouse leukemic cells. 8 Transfer of these RANKL-expressing leukemic cells into immunodeficient recipient mice produced extensive vertebral and long bone destruction suggesting that RANKL-expression by the leukemic cells may have contributed to bone loss. 8 Since osteoporosis-associated fractures are evident in 16% of children and adolescent ALL patients at diagnosis, 2 we asked whether human B-ALL cells could also cause bone destruction.…”

“…We recently reported mechanistic evidence that primary B-ALL cells confer bone destruction in a RANK-RANKL-dependent fashion. 8 Using a mouse model of spon-taneous B-ALL, 9 and B-ALL patient-derived xenograft (PDX) models, we demonstrated that both the mouse and human leukemic cells caused bone destruction in the absence of corticosteroids or other chemotherapeutic agents. 8 We showed that RANKL, the critical regulator of bone resorption, was abundantly expressed by the mouse leukemic cells.…”

“…8 Using a mouse model of spon-taneous B-ALL, 9 and B-ALL patient-derived xenograft (PDX) models, we demonstrated that both the mouse and human leukemic cells caused bone destruction in the absence of corticosteroids or other chemotherapeutic agents. 8 We showed that RANKL, the critical regulator of bone resorption, was abundantly expressed by the mouse leukemic cells. 8 Transfer of these RANKL-expressing leukemic cells into immunodeficient recipient mice produced extensive vertebral and long bone destruction suggesting that RANKL-expression by the leukemic cells may have contributed to bone loss.…”

“…8 Transfer of these RANKL-expressing leukemic cells into immunodeficient recipient mice produced extensive vertebral and long bone destruction suggesting that RANKL-expression by the leukemic cells may have contributed to bone loss. 8 Since osteoporosis-associated fractures are evident in 16% of children and adolescent ALL patients at diagnosis, 2 we asked whether human B-ALL cells could also cause bone destruction. Primary B-ALL cells isolated from patients at diagnosis were injected into the femurs of NOD.Prkdc scid/scid Il2rg tm1Wjl /SzJ (NSG) mice.…”

“…Primary B-ALL cells isolated from patients at diagnosis were injected into the femurs of NOD.Prkdc scid/scid Il2rg tm1Wjl /SzJ (NSG) mice. In this PDX setting, the human B-ALL cells displayed up-regulation of RANKL in the bone microenvironment and conferred both long bone and vertebral trabecular bone destruction 8 (Figure 1). Treatment of PDX recipient mice with the RANKL antagonist recombinant OPG-Fc (rOPG-Fc) conferred robust protection from bone destruction (Figure 1).…”