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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6215-6224.
Prepublished online as a Blood First Edition Paper on October 27, 2008; DOI 10.1182/blood-2008-05-158311.
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Submitted May 22, 2008
Accepted September 12, 2008
Targeting the leukemia microenvironment by CXCR4 inhibition overcomes resistance to kinase inhibitors and chemotherapy in AML
Zhihong Zeng, Yue Xi Shi, Ismael J Samudio, Rui-Yu Wang, Xiaoyang Ling, Olga Frolova, Mark Levis, Joshua B Rubin, Robert R Negrin, Elihu H Estey, Sergej Konoplev, Michael Andreeff, and Marina Konopleva*
Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
Department of Oncology and Hematology, John Hopkins University, Baltimore, MD, United States
Department of Pediatrics, Division of Pediatric Hematology/Oncology, Washington University School of Medicine, St. Louis, MO, United States
Department of Medicine, Division of Bone Marrow Transplantation, Stanford University, Stanford, CA, United States
Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: mkonople{at}mdanderson.org.
SDF-1 /CXCR4 signaling plays a key role in leukemia/bone marrow microenvironment interactions. We previously reported that bone marrow-derived stromal cells inhibit chemotherapy-induced apoptosis in AML. Here we demonstrate that the CXCR4 inhibitor AMD3465 antagonized SDF-1- and stroma-induced chemotaxis and inhibited SDF-1-induced activation of pro-survival signaling pathways in leukemic cells. Further, CXCR4 inhibition partially abrogated the protective effects of stromal cells on chemotherapy-induced apoptosis in AML cells. FLT3 gene mutations activate CXCR4 signaling, and co-culture with stromal cells significantly diminished anti-leukemia effects of FLT3 inhibitors in cells with mutated FLT3. Notably, CXCR4 inhibition increased the sensitivity of FLT3-mutated leukemic cells to the apoptogenic effects of the FLT3 inhibitor sorafenib. Most importantly, in vivo studies demonstrated that AMD3465, alone or in combination with G-CSF, induced mobilization of AML cells into circulation and enhanced anti-leukemic effects of chemotherapy and sorafenib, resulting in markedly reduced leukemia burden and prolonged survival of the animals. These findings indicate that SDF-1/CXCR4 interactions contribute to the resistance of leukemic cells to signal transduction inhibitor- and chemotherapy-induced apoptosis in systems mimicking the physiological microenvironment. Disruption of these interactions with CXCR4 inhibitors represents a novel strategy of sensitizing leukemic cells by targeting their protective bone marrow microenvironment.
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