Christiansen D H, Andersen M K, Pedersen-Bjergaard J
Section of Hematology/Oncology, Cytogenetic Laboratory, Department of Clinical Genetics, Juliane Marie Center, Rigshospitalet, Blegdamsvej, Copenhagen Ø, Denmark.
Leukemia. 2003 Sep;17(9):1813-9. doi: 10.1038/sj.leu.2403054.
The p14(ARF), p15(INK4B), and p16(INK4A) genes are important negative cell-cycle regulators often inactivated by deletions, mutations, or hypermethylation in malignancy. Hypermethylation of the three genes was studied in 81 patients with therapy-related myelodysplasia (t-MDS) or acute myeloid leukemia (t-AML) by methylation-specific PCR, and p15 methylation additionally by bisulfite genomic sequencing. In all, 55 patients disclosed p15 methylation, five patients showed p16 methylation, whereas p14 methylation was not observed. Methylation of p15 was closely associated with deletion or loss of chromosome arm 7q (P=0.0006). In t-MDS, the p15 methylation frequency and the p15 methylation density both increased significantly by stage (P=0.004 and 0.0002), and p15 methylation frequency increased with an increasing percentage of myeloblasts in the bone marrow (P=0.006). In a two-variable Cox model including the percentage of myeloblasts, p15 methylation was an independent prognostic factor (P=0.005). Methylation of p15 was less common in t-AML of subtype M5 than in other FAB subtypes (P=0.03). Methylation of p15 was unrelated to type of previous therapy, to latent period from start of therapy, to platelet count, and to p53 mutations. Inactivation of p15 and deletion of genes on chromosome arm 7q possibly cooperate in leukemogenesis.
p14(ARF)、p15(INK4B)和p16(INK4A)基因是重要的负性细胞周期调节因子，在恶性肿瘤中常因缺失、突变或高甲基化而失活。通过甲基化特异性PCR研究了81例治疗相关的骨髓增生异常综合征(t-MDS)或急性髓系白血病(t-AML)患者中这三个基因的高甲基化情况，并通过亚硫酸氢盐基因组测序额外研究了p15甲基化。共有55例患者出现p15甲基化，5例患者出现p16甲基化，而未观察到p14甲基化。p15甲基化与7号染色体长臂的缺失或丢失密切相关(P = 0.0006)。在t-MDS中，p15甲基化频率和p15甲基化密度均随疾病分期显著增加(P = 0.004和0.0002)，且p15甲基化频率随骨髓中原始粒细胞百分比的增加而升高(P = 0.006)。在包含原始粒细胞百分比的双变量Cox模型中，p15甲基化是一个独立的预后因素(P = 0.005)。p15甲基化在M5亚型的t-AML中比在其他FAB亚型中少见(P = 0.03)。p15甲基化与既往治疗类型、治疗开始后的潜伏期、血小板计数以及p53突变无关。p15失活和7号染色体长臂上基因的缺失可能在白血病发生过程中协同作用。
