Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100.
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-RARalpha knockin mouse were genetically modified with firefly luciferase (APL(luc)) to allow tracking by bioluminescence imaging. Coculture of APL(luc) cells with M2-10B4 stromal cells protected the leukemia cells from chemotherapy-induced apoptosis in vitro. Upon injection into syngeneic recipients, APL(luc) 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.
Nervi
Bruno
B
Division of Oncology, Washington University School of Medicine, St Louis, MO 63110, USA.
Ramirez
Pablo
P
Rettig
Michael P
MP
Uy
Geoffrey L
GL
Holt
Matthew S
MS
Ritchey
Julie K
JK
Prior
Julie L
JL
Piwnica-Worms
David
D
Bridger
Gary
G
Ley
Timothy J
TJ
DiPersio
John F
JF
D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001596:Benzylamines; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D056649:Cathepsin G; D002403:Cathepsins / Q000502:physiology; D003114:Colony-Forming Units Assay; D000080027:Cyclams; D003561:Cytarabine / Q000494:pharmacology; D004357:Drug Synergism; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D021381:Protein Transport; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000502:physiology; D017154:Stromal Cells / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000637:transplantation
D019380:Anti-HIV Agents; D000964:Antimetabolites, Antineoplastic; D001596:Benzylamines; C514936:CXCR4 protein, mouse; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D003561:Cytarabine; D002403:Cathepsins; D012697:Serine Endopeptidases; D056649:Cathepsin G; C534096:Ctsg protein, mouse; C088327:plerixafor