Chronic myelogenous leukemia (CML) is a clonal disorder of the hematopoietic stem cell characterized by a chimeric BCR/ABL gene giving rise to a 210-kD fusion protein with dysregulated tyrosine kinase activity. We investigated the effect of genistein, a protein tyrosine kinase inhibitor, on the in vitro growth of CML and normal marrow-derived multi-potent (colony-forming unit-mix [CFU-Mix]), erythroid (burst-forming unit-erythroid [BFU-E]), and granulocyte-macrophage (colony-forming unit-granulocyte-macrophage [CFU-GM]) hematopoietic progenitors. Continuous exposure of CML and normal marrow to genistein induced a statistically significant and dose-dependent suppression of colony formation. Genistein doses causing 50% inhibition of CML and normal progenitors were not significantly different for CFU-Mix (27 mumol/L v 23 mumol/L), BFU-E (31 mumol/L v 29 mumol/L), and CFU-GM (40 mumol/L v 32 mumol/L).Preincubation of CML and normal marrow with genistein (200 mumol/ L for 1 to 18 hours) induced a time-dependent suppression of progenitor cell growth, while sparing a substantial proportion of long-term culture-initiating cells (LTC-IC) from CML (range, 91% +/- 9% to 32% +/- 3%) and normal marrow (range, 85% +/- 8% to 38% +/- 9%). Analysis of individual CML colonies for the presence of the hybrid BCR/ABL mRNA by reverse transcription-polymerase chain reaction (RT-PCR) showed that genistein treatment significantly reduced the mean +/- SD percentage of marrow BCR/ABL+ progenitors both by continuous exposure (76% +/- 18% v 24% +/- 12%, P < or = .004) or preincubation (75% +/- 16% v 21% +/- 10%, P < or = .002) experiments. Preincubation with genistein reduced the percentage of leukemic LTC-IC from 87% +/- 12% to 37% +/- 12% (P < or = .003). Analysis of individual colonies by cytogenetics and RT-PCR confirmed that genistein-induced increase in the percentage of nonleukemic progenitors was not due to suppression of BCR/ABL transcription.Analysis of nuclear DNA fragmentation by DNA gel electrophoresis and terminal deoxynucleotidyl transferase assay showed that preincubation of CML mononuclear and CD34+ cells with genistein induced significant evidence of apoptosis. These observations show that genistein is capable of (1) exerting a strong antiproliferative effect on CFU-Mix, BFU-E, and CFU-GM while sparing the more primitive LTC-IC and (2) selecting benign hematopoietic progenitors from CML marrow, probably through an apoptotic mechanism.

慢性粒细胞白血病 (CML) 是由能引起210-kD 融合蛋白与酪氨酸激酶活性失调的嵌合 BCR/ABL 基因的特征的造血干细胞的克隆障碍造成的。我们研究酪氨酸激酶抑制剂金雀异黄素对慢性骨髓性白血病细胞和多向造血祖细胞 [CFU-Mix]、定向造血祖细胞[BFU-E])，和粒-单系祖细胞[CFU-GM]体外生长的不同影响。 
慢性骨髓性白血病和正常骨髓细胞持续暴露于金雀异黄素可诱导统计学有显著意义的和集落形成的剂量依赖性抑制。金雀异黄素剂量可50％抑制慢性骨髓性白血病，对正常的祖细胞没有显着的差别，其中CFU-Mix（27 毫摩尔/升对毫摩尔/升）、BFU-E的（微摩尔/升对微摩尔/升），和CFU-GM （40 微摩尔/升对32微摩尔/升）。金雀异黄素(200微摩尔/升，1至18小时)预处理慢性骨髓性白血病和正常骨髓细胞可诱导对祖细胞时间相关性生长抑制，同时保留在慢性骨髓性白血病 (范围 91%+ /-9%至 32%+ /-3%）和正常骨髓 (范围 85%+/-8%至 38%+ /-9%)中一定比例的长期培养起始细胞 (LTC-IC)。 
通过分析可逆转录聚合酶链反应（RT - PCR）的混合BCR / ABL mRNA存在时个别CML的集落，我们发现长期使用金雀异黄素（76％+ / - 18％对24％+ / - 12％，p<或= .004）或用其进行前处理（75％+ / - 16％对21％+ / - 10％，p<或=.002）均可显著降低骨髓BCR / ABL 和祖细胞的SD平均值，金雀异黄素预处理可调白血病LTC-IC值从87％+/ - 12％低至37％+ / - 12％（P < 或 = .003）。利用细胞遗传学和RT - PCR对个别集落的分析证实金雀异黄素诱导的非白血病祖细胞的比例增加，这并非由于BCR / ABL的转录抑制。利用DNA凝胶电泳和末端脱氧核苷酸转移酶检测对核DNA碎裂段的分析表明用金雀异黄素预处理慢性骨髓性白血病单核细胞和CD34 +细胞可显著诱导细胞凋亡。 
这些观察表明，金雀异黄素的作用如下： 
（1）能够对CFU-Mix，BFU-E和CFU-GM发挥强大的抗增殖作用，同时保留了更多的较原始的LTC-IC； 
（2）从慢性骨髓性白血病骨髓中选择良性造血祖细胞，这可能是缘于细胞凋亡的机制。