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^−/−; Prkdc^scid/scid triple mutant (TM) mice and p53^−/−; Prkdc^scid/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.Prkdc^scid/scidIl2rg^tm1Wjl/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.

尽管大多数儿童都能幸存于B细胞急性淋巴细胞白血病（B-ALL），但他们经常遇到与治疗相关的长期健康问题，包括骨质减少和坏死。由于一些儿童在ALL诊断时出现骨折，因此我们考虑了白血病B细胞直接有助于骨骼病理的可能性。为了确定B-ALL驱动的骨破坏的潜在机制，我们研究了p53 ^-/-。Rag2 ^-/- ; Prkdc scid ^/ scid三重突变（TM）小鼠和p53 ^-/- ; Prkdc Scid ^/ Scid自发B-ALL的双突变（DM）小鼠模型。与DM动物相反，白血病TM小鼠显示出脆弱的骨骼，TM白血病细胞过表达Rankl，后者编码核因子κB配体的受体激活剂。RANKL是破骨细胞分化和骨丢失的关键调节剂。TM白血病细胞转移到免疫缺陷受体小鼠中导致小梁骨丢失。为了确定人类B-ALL是否能发挥相似的作用，我们评估了诊断为RANKL表达时分离出的人类B-ALL原代细胞及其移植到NOD后对骨病理的影响。Prkdc Scid ^/ Scid ^{Il2rg tm1Wjl}/ SzJ（NSG）受体小鼠。这些患者来源的异种移植物（PDXs）中，原代B-ALL细胞赋予多发破骨细胞增多，小梁骨丢失，干phy端生长板破坏和脂肪细胞减少的明显骨破坏作用。用RANKL拮抗剂重组骨保护素-Fc（rOPG-Fc）治疗PDX小鼠，即使在沉重的肿瘤负担下，也能保护骨骼免受B-ALL诱导的破坏。我们的数据证明了RANK-RANKL轴在引起B-ALL介导的骨病理学中的关键作用，并为RANKL靶向治疗试验减少这些患者的急性和长期骨破坏提供了临床前支持。