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    New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment

    Access Status
    Fulltext not available
    Authors
    Cheung, Laurence
    Tickner, J.
    Hughes, A.
    Skut, P.
    Howlett, M.
    Foley, B.
    Oommen, J.
    Wells, J.
    He, B.
    Singh, S.
    Chua, G.
    Ford, J.
    Mullighan, C.
    Kotecha, R.
    Kees, U.
    Date
    2018
    Type
    Journal Article
    
    Metadata
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    Citation
    Cheung, L. and Tickner, J. and Hughes, A. and Skut, P. and Howlett, M. and Foley, B. and Oommen, J. et al. 2018. New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment. Leukemia: pp. 1-13.
    Source Title
    Leukemia
    DOI
    10.1038/s41375-018-0144-7
    ISSN
    0887-6924
    School
    School of Pharmacy and Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/69138
    Collection
    • Curtin Research Publications
    Abstract

    © 2018 The Author(s) 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 ?B 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.

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