Vidović Ana, Janković Gradimir, Colović Milica, Tomin Dragica, Perunicić Maja, Bila Jelena, Marković Olivera, Bosković Darinka
Institute of Hematology, Clinical Center of Serbia, Belgrade, Serbia.
Hematology. 2008 Feb;13(1):34-40. doi: 10.1179/102453308X315807.
The chronic phase (CP) of chronic myeloid leukemia (CML) is characterized by the expression of chimeric BCR/ABL gene, extended survival, and profligate growth of maturing granulocyte stemline. The accelerated phase (AP) and blast crisis (BC) of CML are usually manifested by additionally acquired oncogene aberrations, resistance to therapy, advancing anaplasia, progressive organomegaly, and increased blast count. Abnormal expression of some proto-oncogenes may accompany or even precede AP or BC of CML. Our objective was to follow-up oncogene expression over time covering different clinical phases of CML. A total of 85 patients [44 females and 41 males; median age 51 years; range 16-75 years] were studied. At the start of the study, 29 patients were in CP, 25 in an AP, and 31 in BC. Temporal variation in expression (percentage positivity per 1000 analyzed cells) of c-kit, c-myc, H-Ras, cyclin A1, p53, bcl-2 and VEGF oncogenic proteins in CP, AP, and BC of CML was studied by immunohistochemical procedures. This was then correlated with parameters of clinical disease (organomegaly, duration of CP, AP, and BC) and laboratory (Hb, WBC and platelet counts, and the percentage of blasts) data. The level of c-kit expression differed significantly over the course of disease (x(2), p = 0 x 025). Antiapoptotic bcl-2 protein increased significantly with the progression of CML (x(2), p = 0 x 005). The expression of c-myc was most pronounced in the AP (Anova, p = 0 x 033) and then tended to decline. There was no significant difference in the level of expression of H-Ras, cyclin A1 and p53 over the course of disease. The expression of VEGF protein was most pronounced in the AP (Anova, p = 0 x 033) and it was inversely correlated with degree of splenomegaly (Pearson, r = -0 x 400, p = 0 x 011) and overall survival (log rank, p = 0,042).
The changes in oncogene expression, assessed by immunohistochemical approach over the course of CML may have clinical relevance in deciding on and timing of therapy. Temporal distribution of changes in oncoprotein expression in CML requires further study at the molecular level.
慢性髓性白血病（CML）的慢性期（CP）以嵌合性BCR/ABL基因的表达、生存期延长以及成熟粒细胞系的过度增殖为特征。CML的加速期（AP）和急变期（BC）通常表现为额外获得的癌基因畸变、对治疗的抵抗、进行性间变、进行性器官肿大以及原始细胞计数增加。一些原癌基因的异常表达可能伴随甚至先于CML的AP或BC出现。我们的目的是随访CML不同临床阶段随时间变化的癌基因表达情况。共研究了85例患者[44例女性和41例男性；中位年龄51岁；范围16 - 75岁]。研究开始时，29例患者处于CP期，25例处于AP期，31例处于BC期。通过免疫组化方法研究了CML的CP、AP和BC期c-kit、c-myc、H-Ras、细胞周期蛋白A1、p53、bcl-2和VEGF致癌蛋白表达的时间变化（每1000个分析细胞中的阳性百分比）。然后将其与临床疾病参数（器官肿大、CP、AP和BC的持续时间）和实验室数据（血红蛋白、白细胞和血小板计数以及原始细胞百分比）相关联。c-kit表达水平在疾病过程中差异显著（χ²，p = 0.025）。抗凋亡bcl-2蛋白随CML进展显著增加（χ²，p = 0.005）。c-myc的表达在AP期最为明显（方差分析，p = 0.033），然后趋于下降。H-Ras、细胞周期蛋白A1和p53的表达水平在疾病过程中无显著差异。VEGF蛋白的表达在AP期最为明显（方差分析，p = 0.033），并且与脾肿大程度呈负相关（Pearson相关系数，r = -0.400，p = 0.011）以及总生存期呈负相关（对数秩检验，p = 0.042）。
通过免疫组化方法评估的CML病程中癌基因表达的变化在决定治疗方案和治疗时机方面可能具有临床相关性。CML中癌蛋白表达变化的时间分布需要在分子水平上进一步研究。
