Pirson Laurence, Baron Frédéric, Meuris Nathalie, Giet Olivier, Castermans Emilie, Greimers Roland, Di Stefano Ivano, Gothot André, Beguin Yves
Center for Cellular and Molecular Therapy, University of Liège, Belgium.
Stem Cells. 2006 Jul;24(7):1814-21. doi: 10.1634/stemcells.2005-0290. Epub 2006 Apr 13.
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.
将异基因造血细胞移植（HCT），特别是采用非清髓方案的异基因HCT，与酪氨酸激酶抑制剂伊马替尼（格列卫；诺华公司，瑞士巴塞尔，http://www.novartis.com）联合使用，有可能增强对费城染色体阳性白血病的抗白血病活性。然而，由于伊马替尼抑制干细胞因子受体c-kit，它可能会干扰骨髓植入。在本研究中，我们检测了伊马替尼对正常祖细胞功能的影响。伊马替尼降低了动员外周血人CD133(+)细胞的集落形成能力，但未降低长期培养起始细胞的集落形成能力。伊马替尼还降低了细胞因子刺激的CD133(+)细胞的增殖，但未诱导这些细胞凋亡。伊马替尼未改变CD133(+)细胞的极晚期抗原（VLA）-4、VLA-5和CXCR4的表达，但降低了CD133(+)细胞的迁移能力。最后，伊马替尼未降低CD133(+)细胞在接受3或1 Gy全身照射预处理的辐照非肥胖糖尿病/严重联合免疫缺陷/beta2m(null)小鼠中的植入。总之，我们的结果表明，尽管伊马替尼在体外抑制造血祖细胞生长，但它并不干扰造血干细胞植入。
