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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6206-6214.
Prepublished online as a Blood First Edition Paper on December 2, 2008; DOI 10.1182/blood-2008-06-162123.
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MYELOID NEOPLASIA
Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100
Bruno Nervi1,*,
Pablo Ramirez1,*,
Michael P. Rettig1,
Geoffrey L. Uy1,
Matthew S. Holt1,
Julie K. Ritchey1,
Julie L. Prior1,
David Piwnica-Worms2,3,
Gary Bridger4,
Timothy J. Ley1, and
John F. DiPersio1
1 Division of Oncology,
2 Molecular Imaging Center, Mallinckrodt Institute of Radiology, and
3 Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St Louis, MO; and
4 Genzyme, Cambridge, MA
The CXCR4–SDF-1 axis plays a central role in the trafficking and retention of normal and malignant stem cells in the bone marrow (BM) microenvironment. Here, we used a mouse model of acute promyelocytic leukemia (APL) and a small molecule competitive antagonist of CXCR4, AMD3100, to examine the interaction of mouse APL cells with the BM microenvironment. APL cells from a murine cathepsin G-PML-RAR knockin mouse were genetically modified with firefly luciferase (APLluc) to allow tracking by bioluminescence imaging. Coculture of APLluc cells with M2-10B4 stromal cells protected the leukemia cells from chemotherapy-induced apoptosis in vitro. Upon injection into syngeneic recipients, APLluc cells rapidly migrated to the BM followed by egress to the spleen then to the peripheral blood with death due to leukostasis by day 15. Administration of AMD3100 to leukemic mice induced a 1.6-fold increase in total leukocytes and a 9-fold increase of circulating APL blast counts, which peak at 3 hours and return to baseline by 12 hours. Treatment of leukemic mice with chemotherapy plus AMD3100 resulted in decreased tumor burden and improved overall survival compared with mice treated with chemotherapy alone. These studies provide a proof-of-principle for directing therapy to the critical tethers that promote AML-niche interactions.
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