Telethon Kids Cancer Centre, Telethon Kids Institute, University of Western Australia, Perth, WA, Australia.
School of Pharmacy and Biomedical Sciences, Curtin University, Perth, WA, Australia.
Leukemia. 2018 Nov;32(11):2326-2338. doi: 10.1038/s41375-018-0144-7. Epub 2018 May 8.
The microenvironments of leukemia and cancer are critical for multiple stages of malignancies, and they are an attractive therapeutic target. While skeletal abnormalities are commonly seen in children with acute lymphoblastic leukemia (ALL) prior to initiating osteotoxic therapy, little is known about the alterations to the bone marrow microenvironment during leukemogenesis. Therefore, in this study, we focused on the development of precursor-B cell ALL (pre-B ALL) in an immunocompetent BCR-ABL1 model. Here we show that hematopoiesis was perturbed, B lymphopoiesis was impaired, collagen production was reduced, and the number of osteoblastic cells was decreased in the bone marrow microenvironment. As previously found in children with ALL, the leukemia-bearing mice exhibited severe bone loss during leukemogenesis. Leukemia cells produced high levels of receptor activator of nuclear factor κB ligand (RANKL), sufficient to cause osteoclast-mediated bone resorption. In vivo administration of zoledronic acid rescued leukemia-induced bone loss, reduced disease burden and prolonged survival in leukemia-bearing mice. Taken together, we provide evidence that targeting leukemia-induced bone loss is a therapeutic strategy for pre-B ALL.
白血病和癌症的微环境对恶性肿瘤的多个阶段都至关重要，是一个有吸引力的治疗靶点。虽然在开始使用骨毒性治疗之前，患有急性淋巴细胞白血病 (ALL) 的儿童通常会出现骨骼异常，但对于白血病发生过程中骨髓微环境的改变知之甚少。因此，在这项研究中，我们专注于在免疫功能正常的 BCR-ABL1 模型中发生前体 B 细胞 ALL (pre-B ALL)。在这里，我们发现造血受到干扰，B 淋巴细胞生成受损，胶原生成减少，骨髓微环境中的成骨细胞数量减少。正如之前在 ALL 患儿中发现的那样，携带白血病的小鼠在白血病发生过程中出现严重的骨质流失。白血病细胞产生高水平的核因子 κB 受体激活剂配体 (RANKL)，足以引起破骨细胞介导的骨质吸收。唑来膦酸的体内给药可挽救白血病引起的骨质流失，降低白血病小鼠的疾病负担并延长其生存时间。总之，我们提供的证据表明，针对白血病引起的骨质流失是治疗前体 B 细胞 ALL 的一种治疗策略。
