Acquisition of p16INK4A and p15INK4B gene abnormalities between initial diagnosis and relapse in children with acute lymphoblastic leukemia
Acquisition of p16INK4A and p15INK4B gene abnormalities between initial diagnosis and relapse in children with acute lymphoblastic leukemia
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DOI：
10.1182/blood.v93.7.2380.407k27_2380_2385
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发表时间：
1999-04-01
期刊：
影响因子：
20.3
通讯作者：
Hunger, SP
中科院分区：
文献类型：
--
作者：
Maloney, KW;McGavran, L;Hunger, SP
虽然已经确定了许多导致儿童急性淋巴细胞白血病（ALL）发病的体细胞突变，但没有特定的细胞遗传学或分子异常与复发一致相关。p16（INK 4A）（p16）编码p16（INK 4A）和p19（ARF）蛋白，p15（INK 4 B）（P15）基因在初次诊断时，在相当比例的儿童ALL病例中因纯合缺失和/或p15启动子高甲基化而失活。为了确定这些基因的改变是否在疾病进展中起作用，我们分析了一组18个匹配的标本对，这些标本对是从初次诊断和首次骨髓复发时的ALL儿童中收集的纯合p16和/或p15缺失或p15启动子高甲基化。4个样本对在诊断和复发时均含有纯合p16和p15缺失。在诊断时为p16/p15生殖系的14对中，3对ALL发生了p16和p15的纯合缺失，2对发生了纯合p16缺失并在复发时保留了p15生殖系状态。在两名患者中，p15基因启动子高甲基化发生在初次诊断和复发之间。总的来说，18例中有9例存在纯合子p16缺失，18例中有7例存在纯合子p15缺失，8例复发病例中有2例存在p15启动子高甲基化。这些发现表明，p16和/或p15编码的蛋白质的功能丧失在复发性儿童ALL的生物学中起着重要作用，并且在一部分病例中与疾病进展相关。(C)1999年，美国血液学会。
Although numerous somatic mutations that contribute to the pathogenesis of childhood acute lymphoblastic leukemia (ALL) have been identified, no specific cytogenetic or molecular abnormalities are known to be consistently associated with relapse. The p16(INK4A) (p16), which encodes for both p16(INK4A) and p19(ARF) proteins, and p15(INK4B) (P15) genes are inactivated by homozygous deletion and/or p15 promoter hypermethylation in a significant proportion of cases of childhood ALL at the time of initial diagnosis. To determine whether alterations in these genes play a role in disease progression, we analyzed a panel of 18 matched specimen pairs collected from children with ALL at the time of initial diagnosis and first bone marrow relapse for homozygous p16 and/or p15 deletions or p15 promoter hypermethylation. Four sample pairs contained homozygous p16 and p15 deletions at both diagnosis and relapse. Among the 14 pairs that were p16/p15 germline at diagnosis, three ALLs developed homozygous deletions of both p16 and p15, and two developed homozygous p16 deletions and retained p15 germline status at relapse. In two patients, p15 promoter hypermethylation developed in the interval between initial diagnosis and relapse. In total, homozygous p16 deletions were present in nine of 18 cases, homozygous p15 deletions in seven of 18 cases, and p15 promoter hypermethylation in two of eight cases at relapse. These findings indicate that loss of function of proteins encoded by p16 and/or p15 plays an important role in the biology of relapsed childhood ALL, and is associated with disease progression In a subset of cases. (C) 1999 by The American Society of Hematology.