Shteper P J, Siegfried Z, Asimakopoulos F A, Palumbo G A, Rachmilewitz E A, Ben-Neriah Y, Ben-Yehuda D
Department of Hematology, Hadassah University Hospital, Hebrew University-Hadassah Medical School, Jerusalem, Israel.
Leukemia. 2001 Apr;15(4):575-82. doi: 10.1038/sj.leu.2402026.
In human Ph-positive leukemia there is a clear association of different forms of the BCR-ABL oncogene with distinct types of leukemia. The P190 form of BCR-ABL is rarely observed in chronic myeloid leukemia (CML) but is present in 50% of Ph-positive acute lymphoblastic leukemia (ALL). In contrast, the P210 form is observed both in CML and 50% of Ph-positive ALL. Methylation of the proximal promoter of the ABL1 gene has been shown to be a nearly universal event associated with clinical progression of CML. This raises the question of whether methylation of the ABL1 promoter is an epigenetic modification also associated with Ph-positive ALL. To study this issue, we used methylation-specific PCR and bisulfite sequencing to determine the methylation status of the ABL1 promoter in 18 Ph-positive ALL samples. We report here that gene-specific ABL1 promoter methylation is associated mainly with the P210 form of BCR-ABL and not the P190 form. While six out of the seven P210-positive ALL samples had ABL1 promoter methylation, none of the 11 P190-positive ALL samples demonstrated ABL1 promoter methylation. In addition, we estimated the extent and relative abundance of ABL1 promoter methylation in several Ph-positive ALL samples and compared it to the methylation pattern in chronic, accelerated and blastic crisis phases of CML. We put forth a model that correlates the different types of leukemias with the different levels of ABL1 promoter methylation.
在人类Ph阳性白血病中，不同形式的BCR-ABL癌基因与不同类型的白血病之间存在明确关联。BCR-ABL的P190形式在慢性髓性白血病（CML）中很少见，但在50%的Ph阳性急性淋巴细胞白血病（ALL）中存在。相反，P210形式在CML和50%的Ph阳性ALL中均有观察到。ABL1基因近端启动子的甲基化已被证明是与CML临床进展相关的几乎普遍存在的事件。这就提出了一个问题，即ABL1启动子的甲基化是否也是一种与Ph阳性ALL相关的表观遗传修饰。为了研究这个问题，我们使用甲基化特异性PCR和亚硫酸氢盐测序来确定18例Ph阳性ALL样本中ABL1启动子的甲基化状态。我们在此报告，基因特异性的ABL1启动子甲基化主要与BCR-ABL的P210形式相关，而不是P190形式。在7例P210阳性ALL样本中，有6例存在ABL1启动子甲基化，而11例P190阳性ALL样本中均未显示ABL1启动子甲基化。此外，我们估计了几个Ph阳性ALL样本中ABL1启动子甲基化的程度和相对丰度，并将其与CML慢性期、加速期和急变期的甲基化模式进行了比较。我们提出了一个模型，将不同类型的白血病与ABL1启动子甲基化的不同水平联系起来。
