Jiang Guanchao, Yang Fan, Li Marilyn, Weissbecker Karen, Price Sherrie, Kim K C, La Russa Vincent F, Safah Hana, Ehrlich Melanie
Tulane Cancer Center and Humon Genetics Program, Tulane Medical School, New Orleans, Lousiana 70112, USA.
Cancer Biol Ther. 2003 Jan-Feb;2(1):103-8. doi: 10.4161/cbt.240.
Very promising results have been obtained in clinical trials on chronic-phase chronic myeloid leukemia (CP-CML) patients treated with imatinib mesylate (IM; Gleevecr, STI571), a BCR-ABL tyrosine kinase inhibitor. However, we found that IM caused considerable inhibition of normal hematopoietic progenitor cells upon treating control bone marrow (BM) cultures. In vitro IM treatment gave a decrease in the yield and size of colonies from BM of untreated CP-CML patients that was only two to three times that from the normal samples. Moreover, about 30% of myeloid progenitors (CFU-GM) from CML BM still formed colonies in the presence of IM, most of which had BCR-ABL RNA. About half of these treated colonies also displayed methylation of the internal ABL Pa promoter, a CML-specific epigenetic alteration, which was used in this study as a marker for BCR-ABL translocation-containing cells. However, ~5-8% of the treated or the untreated CML BM-derived colonies had no detectable BCR-ABL RNA by two or three rounds of RT-PCR despite being positive for the internal standard RNA and displaying hallmarks of CML, either t(9;22)(q34;ql 1) or ABL Pa methylation. Our results indicate that IM is only partially specific for CML progenitor cells compared to normal hematopoietic progenitor cells and suggest that some CML cells may have a silent BCR-ABL oncogene that could interfere with therapy.
在使用甲磺酸伊马替尼（IM；格列卫，STI571）——一种BCR-ABL酪氨酸激酶抑制剂治疗慢性期慢性髓性白血病（CP-CML）患者的临床试验中，已取得了非常有前景的结果。然而，我们发现，在处理对照骨髓（BM）培养物时，IM对正常造血祖细胞有相当程度的抑制作用。体外IM处理使未经治疗的CP-CML患者骨髓中的集落产量和大小降低，降低程度仅为正常样本的两到三倍。此外，在IM存在的情况下，约30%的CML骨髓髓系祖细胞（CFU-GM）仍能形成集落，其中大多数具有BCR-ABL RNA。这些经处理的集落中约有一半还显示出内部ABL Pa启动子的甲基化，这是一种CML特异性表观遗传改变，在本研究中用作含BCR-ABL易位细胞的标志物。然而，尽管经两轮或三轮逆转录聚合酶链反应（RT-PCR）检测，约5-8%经处理或未经处理的CML骨髓来源集落没有可检测到的BCR-ABL RNA，但它们对内参RNA呈阳性，并且表现出CML的特征，即t(9;22)(q34;q11)或ABL Pa甲基化。我们的结果表明，与正常造血祖细胞相比，IM对CML祖细胞仅具有部分特异性，并提示一些CML细胞可能具有沉默的BCR-ABL癌基因，这可能会干扰治疗。
