DISSECTION OF THE PRE-B LEUKAEMIA BONE MARROW MICROENVIRONMENT

Abstract

The microenvironments of leukaemia and cancer are critical for multiple stages of malignancies, and they are an attractive therapeutic target. Clinical studies in children diagnosed with acute lymphoblastic leukaemia (ALL) have clearly demonstrated defects in bone marrow microenvironment, yet little is known about the contribution of the normal bone marrow cells during the development of the disease, progression and relapse. It remains unclear whether the clinical symptoms of increased bone fragility and reduced bone mineral density should be treated at diagnosis, and whether such treatments would have any impact on the leukaemia progression. To elucidate the influence of ALL on haematopoiesis and the microenvironment, we studied the development of pre-B cell ALL (pre-B ALL) in an immunocompetent BCR-ABL1+ model. We found that haematopoiesis was perturbed, B lymphopoiesis was impaired, collagen production was reduced, and the number of osteoblastic cells was decreased in the bone marrow microenvironment. Moreover, the leukaemia-bearing mice exhibited severe bone loss during leukaemogenesis, which is consistent with clinical data in paediatric ALL. We showed that leukaemia cells produce receptor activator of nuclear factor κB ligand (RANKL), and observed osteoclast-mediated bone resorption. We demonstrated that inhibition of osteoclasts with zoledronic acid in leukaemia mice significantly reduced disease burden and prolonged survival. Our study reveals the impact of pre-B ALL development on haematopoiesis, bones and bone marrow microenvironment. It provides evidence for targeting leukaemia-induced bone loss as a novel therapeutic strategy for patients. 1