Impact of CXCR4 inhibition on FLT3-ITD−positive human AML blasts
Received 15 June 2009; received in revised form 13 December 2009; accepted 14 December 2009. published online 25 December 2009.
Objective
Internal tandem duplication (ITD) mutations of the FLT3 receptor are associated with a high incidence of relapse in acute myeloid leukemia (AML). Expression of the CXCR4 receptor in FLT3-ITD−positive AML is correlated with poor outcome, and inhibition of CXCR4 was shown to sensitize AML blasts toward chemotherapy. The aim of this study was to evaluate the impact of FLT3-ITD on cell proliferation and CXCR4-dependent migration in human hematopoietic progenitor cells and to investigate their response to CXCR4 inhibition.
Materials and Methods
We used primary blasts from patients with FLT3-ITD or FLT3 wild-type AML. In addition, human CD34+ hematopoietic progenitor cells were transduced to >70% with retroviral vectors containing human FLT3-ITD.
Results
We found that FLT3-ITD transgene overexpressing human hematopoietic progenitor cells show strongly reduced migration toward stromal-derived factor−1 in vitro and display significantly reduced bone marrow homing in nonobese diabetic severe combined immunodeficient mice. Cocultivation of FLT3-ITD−positive AML blasts or hematopoietic progenitor cells on bone marrow stromal cells resulted in a strong proliferation advantage and increased early cobblestone area−forming cells compared to FLT3−wild-type AML blasts. Addition of the CXCR4 inhibitor AMD3100 to the coculture significantly reduced both cobblestone area−forming cells and proliferation of FLT3-ITD−positive cells, but did not affect FLT3−wild-type cells—highlighting the critical interaction between CXCR4 and FLT3-ITD.
Conclusion
CXCR4 inhibition to decrease cell proliferation and to control the leukemic burden may provide a novel therapeutic strategy in patients with advanced FLT3-ITD−positive AML.
aDepartment of Pediatrics, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
bDFG Research Center and Cluster of Excellence for Regenerative Therapies Dresden, Technical University Dresden, Dresden, Germany
cLaboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., USA
dMedical Clinic I, University Clinic Carl Gustav Carus Dresden, Dresden, Germany
Offprint requests to: Sebastian Brenner, M.D., Department of Pediatrics, University Clinic Carl Gustav Carus Dresden, Building 21, Fetscherstr 74, 01307 Dresden, Germany
∗ Drs. Jacobi and Thieme contributed equally to this work.
† Drs. Ryser and Brenner contributed equally to this work.
ABSTRACT