Gaiger A, Henn T, Hörth E, Geissler K, Mitterbauer G, Maier-Dobersberger T, Greinix H, Mannhalter C, Haas O A, Lechner K, Lion T
CCRI, Children's Cancer Research Institute, St Anna Children's Hospital, Vienna, Austria.
Blood. 1995 Sep 15;86(6):2371-8.
The translocation t(9;22) in chronic myeloid leukemia (CML) generates a bcr-abl fusion gene that codes for an aberrant chimeric mRNA. Cell lines established from CML patients in blast crisis show higher expression of this aberrant bcr-abl transcript than cells from patients in chronic phase of the disease. This observation provided the stimulus to investigate whether increased expression of the aberrant bcr-abl fusion transcript is critical to the progression of CML from chronic phase to blast crisis. We have monitored the bcr-abl mRNA expression in 25 patients by serial quantitative polymerase chain reaction analyses during a follow-up period of 12 to 156 months after diagnosis, with a median observation time of 28 months. In all patients who have shown disease progression to accelerated phase (n = 4) or blast crisis (n = 7), an increase in bcr-abl mRNA expression was detected up to 16 months before laboratory or clinical parameters showed phenotypic transformation of the malignant clone. To investigate whether the elevated levels of bcr-abl mRNA reflected an increase in the proportion of leukemic cells in the samples analyzed or primarily enhanced transcriptional activity of the bcr-abl fusion gene, we performed quantitative analyses of the bcr-abl gene at the DNA level and of the Ph chromosome at the cytogenetic level and compared these data with steady-state bcr-abl mRNA levels. We show that increased levels of the bcr-abl transcript did not reflect increased proportions of leukemic cells but elevated steady-state levels of the chimeric mRNA in the malignant cells before disease progression. Therefore, our data strongly suggest that an increase of the chimeric mRNA expression in the leukemic cells precedes the phenotypic transformation of the malignant clone.
慢性髓性白血病（CML）中的t(9;22)易位产生一种bcr-abl融合基因，该基因编码异常的嵌合mRNA。从处于急变期的CML患者建立的细胞系显示，这种异常的bcr-abl转录本的表达高于疾病慢性期患者的细胞。这一观察结果促使人们研究异常的bcr-abl融合转录本表达增加是否对CML从慢性期进展到急变期至关重要。我们通过连续定量聚合酶链反应分析，在诊断后的12至156个月随访期内监测了25例患者的bcr-abl mRNA表达，中位观察时间为28个月。在所有已显示疾病进展至加速期（n = 4）或急变期（n = 7）的患者中，在实验室或临床参数显示恶性克隆的表型转变前16个月就检测到bcr-abl mRNA表达增加。为了研究bcr-abl mRNA水平升高是否反映了所分析样本中白血病细胞比例的增加，还是主要反映了bcr-abl融合基因转录活性的增强，我们在DNA水平对bcr-abl基因进行了定量分析，并在细胞遗传学水平对Ph染色体进行了分析，并将这些数据与稳态bcr-abl mRNA水平进行了比较。我们发现，bcr-abl转录本水平的升高并不反映白血病细胞比例的增加，而是反映了疾病进展前恶性细胞中嵌合mRNA稳态水平的升高。因此，我们的数据强烈表明，白血病细胞中嵌合mRNA表达的增加先于恶性克隆的表型转变。
