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Type: Journal article
Title: New therapeutic opportunities from dissecting the pre-B leukemia bone marrow microenvironment
Author: Cheung, L.C.
Tickner, J.
Hughes, A.M.
Skut, P.
Howlett, M.
Foley, B.
Oommen, J.
Wells, J.E.
He, B.
Singh, S.
Chua, G.-A.
Ford, J.
Mullighan, C.G.
Kotecha, R.S.
Kees, U.R.
Citation: Leukemia, 2018; 32(11):2326-2338
Publisher: Springer
Issue Date: 2018
ISSN: 0887-6924
Statement of
Laurence C. Cheung, Jennifer Tickner, Anastasia M. Hughes, Patrycja Skut, Meegan Howlett, Bree Foley, Joyce Oommen, Julia E. Wells, Bo He, Sajla Singh, Grace-Alyssa Chua, Jette Ford, Charles G. Mullighan, Rishi S. Kotecha, Ursula R. Kees
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.
Keywords: Bone Marrow Cells
Cell Line
Bone Marrow
Mice, Inbred C57BL
Bone Resorption
RANK Ligand
Precursor Cell Lymphoblastic Leukemia-Lymphoma
HEK293 Cells
Tumor Microenvironment
Zoledronic Acid
Rights: © The Author(s) 2018. This article is published with open access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons. org/licenses/by/4.0/.
DOI: 10.1038/s41375-018-0144-7
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