Despite inhibition of hematopoietic progenitor cell growth in vitro, the tyrosine kinase inhibitor imatinib does not impair engraftment of human CD133+ cells into NOD/SCIDbeta2mNull mice.
There is potential interest for combining allogeneic hematopoietic cell transplantation (HCT), and particularly allogeneic HCT with a nonmyeloablative regimen, to the tyrosine kinase inhibitor imatinib (Glivec; Novartis, Basel, Switzerland, http://www.novartis.com) in order to maximize anti-leukemic activity against Philadelphia chromosome-positive leukemias. However, because imatinib inhibits c-kit, the stem cell factor receptor, it could interfere with bone marrow engraftment. In this study, we examined the impact of imatinib on normal progenitor cell function. Imatinib decreased the colony-forming capacity of mobilized peripheral blood human CD133(+) cells but not that of long-term culture-initiating cells. Imatinib also decreased the proliferation of cytokine-stimulated CD133(+) cells but did not induce apoptosis of these cells. Expression of very late antigen (VLA)-4, VLA-5, and CXCR4 of CD133(+) cells was not modified by imatinib, but imatinib decreased the ability of CD133(+) cells to migrate. Finally, imatinib did not decrease engraftment of CD133(+) cells into irradiated nonobese diabetic/severe combined immunodeficient/beta2m(null) mice conditioned with 3 or 1 Gy total body irradiation. In summary, our results suggest that, despite inhibition of hematopoietic progenitor cell growth in vitro, imatinib does not interfere with hematopoietic stem cell engraftment.
Pirson
Laurence
L
Center for Cellular and Molecular Therapy, University of Liège, Belgium.
Baron
Frédéric
F
Meuris
Nathalie
N
Giet
Olivier
O
Castermans
Emilie
E
Greimers
Roland
R
Di Stefano
Ivano
I
Gothot
André
A
Beguin
Yves
Y
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D001773:Blood Cells / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D005312:Fetal Blood / Q000187:drug effects; D005353:Fibronectins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism*; D020544:Graft vs Leukemia Effect / Q000187:drug effects; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D000068877:Imatinib Mesylate; D039041:Integrin alpha4beta1 / Q000378:metabolism; D039081:Integrin alpha5beta1 / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000517:prevention & control; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010455:Peptides / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology*; D019718:Receptors, CXCR4 / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000071916:AC133 Antigen; D015703:Antigens, CD; D001549:Benzamides; D005353:Fibronectins; D006023:Glycoproteins; D039041:Integrin alpha4beta1; D039081:Integrin alpha5beta1; C000606023:PROM1 protein, human; D010455:Peptides; D010879:Piperazines; C000606024:Prom1 protein, mouse; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019718:Receptors, CXCR4; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor