Serra A, Gottardi E, Della Ragione F, Saglio G, Iolascon A
Dipartimento Scienze Biomediche e Oncologia Umana, Università di Torino, Ospedale San Luigi Gonzaga, Orbassano, Turin, Italy.
Br J Haematol. 1995 Nov;91(3):625-9. doi: 10.1111/j.1365-2141.1995.tb05358.x.
Recent data suggest that homozygous deletion of the cyclin-dependent kinase 4 inhibitor gene (CDKN2), a putative tumour suppressor gene located on chromosome 9p21, represents a common genetic event in human cancer. As the molecular basis of the evolution of chronic myelogenous leukaemia (CML) into blast crisis remains largely unknown, we decided to investigate if the occurrence of similar deletions could represent one of the mechanisms underlying the disease progression. Whereas none of 22 chronic phase CML cases examined showed alterations, we found that 3/17 total blast crisis examined (18%) showed a homozygous deletion of the CDKN2 gene. The deletions were restricted to cases of lymphoid blast crisis, being present in 3/8 (40%) of the lymphoid and in none of the nine myeloid cases examined. The fact that the chronic phase DNA obtained at diagnosis in one of the cases lacks the homozygous deletion observed in blast crisis, suggests that the final deletion event took place concomitantly with the progression of the disease. Furthermore, the analysis of polymorphic regions on chromosome 9p21 flanking at both sides the CDKN2 gene, showed that deletions at 9p21 differ between cases and are characterized by a wide range of extensions. A concomitant search for a possible involvement of the p53 tumour suppressor gene in the same series of patients showed mutations of the gene and loss of heterozygosity at 17p only in myeloid blast crisis, suggesting the presence of distinct molecular pathways in the pathogenesis of lymphoid and myeloid blast crisis.
近期数据表明，细胞周期蛋白依赖性激酶4抑制剂基因（CDKN2）纯合缺失是人类癌症中常见的遗传事件，该基因是定位于9号染色体p21区域的一个假定肿瘤抑制基因。由于慢性髓性白血病（CML）进展为急变期的分子基础仍不清楚，我们决定研究类似缺失的发生是否可能是疾病进展的潜在机制之一。在检测的22例慢性期CML病例中均未发现改变，但我们发现，在检测的17例急变期病例中有3例（18%）显示CDKN2基因纯合缺失。这些缺失仅限于淋巴母细胞急变期病例，在8例淋巴母细胞急变期病例中有3例（40%）存在缺失，而在检测的9例髓系急变期病例中均未发现。其中1例病例诊断时获得的慢性期DNA缺乏急变期观察到的纯合缺失，这一事实表明最终的缺失事件与疾病进展同时发生。此外，对CDKN2基因两侧9号染色体p21多态性区域的分析表明，9p21区域的缺失在不同病例中有所不同，其特征是缺失范围广泛。在同一组患者中同时寻找p53肿瘤抑制基因可能的参与情况，结果显示仅在髓系急变期病例中存在该基因的突变和17p杂合性缺失，这表明淋巴母细胞急变期和髓系急变期发病机制中存在不同的分子途径。
