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PMID: 19050309 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100.

Blood ·Vol. 113 ·No. 24 ·2009-06-11 ·Pages 6206-14

Nervi B, Ramirez P, Rettig MP, Uy GL, Holt MS, Ritchey JK, Prior JL, Piwnica-Worms D, Bridger G, Ley TJ, DiPersio JF

Abstract

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.

MeSH Terms
Animals Anti-HIV Agents/pharmacology Antimetabolites, Antineoplastic/pharmacology Apoptosis/drug effects Benzylamines Bone Marrow/drug effects,metabolism Cathepsin G Cathepsins/physiology Colony-Forming Units Assay Cyclams Cytarabine/pharmacology Drug Synergism Hematopoietic Stem Cell Mobilization Hematopoietic Stem Cells/metabolism Heterocyclic Compounds/pharmacology Leukemia, Experimental/drug therapy,metabolism,pathology Leukemia, Promyelocytic, Acute/drug therapy,metabolism,pathology Mice Mice, Inbred C57BL Protein Transport Receptors, CXCR4/antagonists & inhibitors,genetics,metabolism Serine Endopeptidases/physiology Stromal Cells/drug effects,metabolism Tumor Cells, Cultured/transplantation
Chemicals
Anti-HIV Agents Antimetabolites, Antineoplastic Benzylamines CXCR4 protein, mouse Cyclams Heterocyclic Compounds Receptors, CXCR4 Cytarabine Cathepsins Serine Endopeptidases Cathepsin G Ctsg protein, mouse plerixafor
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Nervi Bruno
Division of Oncology, Washington University School of Medicine, St Louis, MO 63110, USA.
Ramirez Pablo
Rettig Michael P
Uy Geoffrey L
Holt Matthew S
Ritchey Julie K
Prior Julie L
Piwnica-Worms David
Bridger Gary
Ley Timothy J
DiPersio John F
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
1528-0020
DOI
10.1182/blood-2008-06-162123
Published
2009-06-11
Epub
2008-00-02
Pages
6206-14
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC2699239
Subset
IM
Grants
NCI NIH HHS · P50 CA094056 · United States
NCI NIH HHS · R21 CA110489 · United States
NCI NIH HHS · R01 CA083845 · United States
NCI NIH HHS · R01 CA83845 · United States
NCI NIH HHS · P01 CA101937 · United States
NCI NIH HHS · P50 CA94056 · United States
NCI NIH HHS · P01 CA0101937 · United States
Corrections
CommentIn
PMID: 19520813
CommentIn
PMID: 19628718
External Links
PubMed source DOI: 10.1182/blood-2008-06-162123 PMC Full Text View journal details
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