Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro
Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro
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DOI：
10.1182/blood.v99.1.319
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发表时间：
2002-01-01
期刊：
影响因子：
20.3
通讯作者：
Holyoake, TL
中科院分区：
文献类型：
--
作者：
Graham, SM;Jorgensen, HG;Holyoake, TL
在临床试验中，酪氨酸激酶抑制剂STI 571已被证明在降低慢性髓性白血病（CML）的白血病细胞负荷方面非常有效。测定CML CD 34（+）祖细胞对STI 571的总体敏感性以及细胞死亡依赖于细胞周期状态的程度。来自慢性期CML患者外周血和粒细胞集落刺激因子动员的健康供体的干细胞（Lin（-）CD 34（+））用羧基荧光素二乙酸琥珀酰亚胺基二酯染料标记，以高分辨率跟踪细胞分裂。然后将它们在有和没有生长因子+/-STI 571的情况下培养3天。培养后，通过荧光激活的细胞分选将细胞分离成活细胞群。用于基因分型的静止细胞与循环细胞。对于健康对照，在生长因子的存在下，STI 571既不影响细胞周期动力学，也不影响活细胞的恢复。在缺乏生长因子的情况下，正常细胞无法分裂。对于CML样本，在存在或不存在生长因子的情况下，对STI 571的反应是可变的。在最敏感的病例中，STI 571几乎杀死了所有分裂细胞;然而，在未分裂峰中回收了大量存活的CD 34（+）细胞，并证实其为白血病克隆的一部分。STI 571似乎也表现出对静止群体的抗增殖活性。这些研究证实，即使在生长因子和STI 571存在下，CML干细胞在静止状态下仍保持活力。尽管在体内有显著的短期反应，但这种体外对STI 571的不敏感性，与其已证实的抗增殖活性相结合，可能在长期治疗后转化为疾病复发。（血。2002;99：319-325）（C）2002年由美国血液学会。
In clinical trials, the tyrosine kinase inhibitor STI571 has proven highly effective in reducing leukemic cell burden in chronic myeloid leukemia (CML). The overall sensitivity of CML CD34(+) progenitor cells to STI571 and the degree to which cell death was dependent on cell cycle status were determined. Stem cells (Lin(-)CD34(+)) from the peripheral blood of patients with CML in chronic phase and from granulocyte-colony-stimulating factor-mobilized healthy donors were labeled with carboxy-fluorescein diacetate succinimidyl diester dye to enable high-resolution tracking of cell division. Then they were cultured for 3 days with and without growth factors +/- STI571. After culture, the cells were separated by fluorescence-activated cell sorting into populations of viable! quiescent versus cycling cells for genotyping. For healthy controls, in the presence of growth factors, STI571 affected neither cell cycle kinetics nor recovery of viable cells. In the absences of growth factors, normal cells were unable to divide. For CML samples, in the presence or absence of growth factors, the response to STI571 was variable. In the most sensitive cases, STI571 killed almost all dividing cells; however, a significant population of viable CD34(+) cells was recovered in the undivided peak and confirmed to be part of the leukemic clone. STI571 also appeared to exhibit antiproliferative activity on the quiescent population. These studies confirm that CML stem cells remain viable in a quiescent state even in the presence of growth factors and STI571. Despite dramatic short-term responses in vivo, such in vitro insensitivity to STI571, in combination with its demonstrated antiproliferative activity, could translate into disease relapse after prolonged therapy. (Blood. 2002;99:319-325) (C) 2002 by The American Society of Hematology.