Abstract
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.
Highlights
These authors contributed : RS Kotecha, UR Kees.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Acute lymphoblastic leukemia (ALL) is the most common cancer among children and remains a frequent cause of death from cancer before 20 years of age [1, 2]
Normal bone marrow cells were transduced with MSCV-BCR-ABL1-IRES-mCherry retrovirus and transplanted into lethally irradiated recipients, and they developed pre-B ALL
The bone marrow microenvironment (BMM) is essential for normal hematopoiesis, and for leukemogenesis [26, 49, 50]
Summary
These authors contributed : RS Kotecha, UR Kees. A significant gain in clinical outcome has been achieved through better prediction of survival, based on refined risk stratification of patients. Outcomes in high-risk subgroups and salvage rates remain poor, including those with BCR-ABL1 fusion, BCR-ABL1like ALL, T-cell ALL (T-ALL), and infant ALL [1, 5, 7,8,9]. Further intensification of current multi-agent chemotherapy is associated with increased toxicity, and hematopoietic stem cell transplantation is an option for patients who are considered to be at very high risk of treatment failure
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