Holtz Melissa, Forman Stephen J, Bhatia Ravi
Division of Hematology and Hematopoietic Cell Transplantation, Department of Hematopoietic Stem Cell and Leukemia Research, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
Cancer Res. 2007 Feb 1;67(3):1113-20. doi: 10.1158/0008-5472.CAN-06-2014.
The BCR/ABL tyrosine kinase inhibitor imatinib mesylate is highly effective in the treatment of chronic myelogenous leukemia (CML) but fails to eliminate all leukemia cells. Residual leukemia stem and progenitor cells persist in imatinib-responsive patients and may be a potential source of relapse. Previous studies indicate that imatinib preferentially targets dividing cells, and nondividing progenitor cells are resistant to imatinib-mediated apoptosis. We investigated whether growth factor stimulation of progenitor proliferation could reduce the number of residual nondividing cells remaining after imatinib treatment. CML and normal CD34(+) cells were labeled with 5-(and 6-)-carboxyfluorescein diacetate succinimidyl ester (CFSE) to track cell division and cultured in low or high concentrations of growth factor to determine effects of growth factor stimulation on nondividing cells. High growth factor concentrations significantly enhanced CML proliferation with or without imatinib treatment and significantly reduced the number of viable, nondividing CFSE bright cells remaining after imatinib exposure. Stimulation with high growth factor before imatinib treatment further reduced the number of residual nondividing CML CD34(+) cells. Importantly, clinically achievable concentrations of granulocyte macrophage colony-stimulating factor alone or in combination with granulocyte colony-stimulating factor also significantly reduced nondividing CML CD34(+) cells. These results support the potential efficacy of growth factor stimulation in reducing the residual leukemia progenitor population in imatinib-treated patients.
BCR/ABL酪氨酸激酶抑制剂甲磺酸伊马替尼在治疗慢性粒细胞白血病（CML）方面非常有效，但无法清除所有白血病细胞。残留的白血病干细胞和祖细胞在对伊马替尼有反应的患者体内持续存在，可能是复发的潜在来源。先前的研究表明，伊马替尼优先靶向分裂细胞，而非分裂祖细胞对伊马替尼介导的细胞凋亡具有抗性。我们研究了生长因子刺激祖细胞增殖是否能减少伊马替尼治疗后残留的非分裂细胞数量。用5-（和6-）羧基荧光素二乙酸琥珀酰亚胺酯（CFSE）标记CML和正常CD34(+)细胞以追踪细胞分裂，并在低浓度或高浓度生长因子中培养，以确定生长因子刺激对非分裂细胞的影响。无论有无伊马替尼治疗，高浓度生长因子均能显著增强CML增殖，并显著减少伊马替尼处理后存活的、非分裂的CFSE高荧光细胞数量。在伊马替尼治疗前用高浓度生长因子刺激可进一步减少残留的非分裂CML CD34(+)细胞数量。重要的是，临床可达到浓度的粒细胞巨噬细胞集落刺激因子单独使用或与粒细胞集落刺激因子联合使用也能显著减少非分裂CML CD34(+)细胞。这些结果支持生长因子刺激在减少伊马替尼治疗患者残留白血病祖细胞群体方面的潜在疗效。
