Acquired loss of p53 induces blastic transformation in p210bcr/abl-expressing hematopoietic cells:: a transgenic study for blast crisis of human CML
Acquired loss of p53 induces blastic transformation in p210bcr/abl-expressing hematopoietic cells:: a transgenic study for blast crisis of human CML
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DOI：
10.1182/blood.v95.4.1144.004k04_1144_1150
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发表时间：
2000-02-15
期刊：
影响因子：
20.3
通讯作者：
Hirai, H
中科院分区：
文献类型：
--
作者：
Honda, H;Ushijima, T;Hirai, H
慢性粒细胞白血病（CML）开始于缓慢的慢性期，但不可避免地发展为致命的急变期。虽然费城染色体，产生p210（bcr/abl）是一个独特的染色体异常在慢性期，额外的染色体异常经常检测到的急变，这表明叠加的遗传事件是疾病进展的原因。为了研究p53的缺失是否在CML的进化中起作用，我们将p210（bcr/abl）转基因的CML细胞与p210（bcr/abl）转基因的CML细胞进行杂交。（BCR/ABL）-转基因、p53-杂合（p53（+/-））小鼠和p210（bcr/abl）-转基因、p53-杂合（p53（+/-））小鼠（BCR/ABL（tg）/-p53（+/-））小鼠，其中残留的正常p53等位基因的体细胞改变直接废除p53功能。与野生型（BCWABL（-/-）p53（+/+））、p53杂合型（BCR/ABL（-/-）p53（+/-））和p210（bcr/abl）转基因（BCR/ABL（tg/-）p53（+/+））同窝小鼠相比，BCR/ABL（tg/-）p53（+/-）小鼠在短时间内死亡。它们具有快速的原始细胞增殖，在此之前出现类似于人CML的骨髓增殖性疾病的亚临床或临床体征。原始细胞是克隆性起源的，表达p210（bcr/abl）并具有增加的激酶活性。有趣的是，残留的正常p53等位基因在肿瘤组织中频繁且优先丢失，这意味着在表达p210（bcr/abl）的造血细胞中存在某种促进p53等位基因丢失的机制。我们的研究提供了体内证据，即获得性p53缺失有助于表达p21（bcr/abl）的造血细胞的急变，并为人类CML急变的分子机制提供了见解。
Chronic myelogenous leukemia (CML) begins with an indolent chronic phase but inevitably progresses to a fatal blast crisis. Although the Philadelphia chromosome, which generates p210(bcr/abl) is a unique chromosomal abnormality in the chronic phase, additional chromosomal abnormalities are frequently detected in the blast crisis, suggesting that superimposed genetic events are responsible for disease progression. To investigate whether loss of p53 plays a role in the evolution of CML, we crossmated p210(bcr/abl)-transgenic (BCR/ABL(tg/-)) mice with p53-heterozygous (p53(+/-)) mice and generated p210(bcr/abl)-transgenic, p53-heterozygous (BCR/ABL(tg)/-p53(+/-)) mice, in which a somatic alteration in the residual normal p53 allele directly abrogates p53 function. The BCR/ABL(tg/-)p53(+/-) mice died in a short period compared with their wild-type (BCWABL(-/-)p53(+/+)), p53 heterozygous (BCR/ABL(-/-)p53(+/-)), and p210(bcr/abl) transgenic (BCR/ABL(tg/-)p53(+/+)) litter mates. They had rapid proliferation of blast cells, which was preceded by subclinical or clinical signs of a myeloproliferative disorder resembling human CML, The blast cells were clonal in origin and expressed p210(bcr/abl) with an increased kinase activity. Interestingly, the residual normal p53 allele was frequently and preferentially lost in the tumor tissues, implying that a certain mechanism facilitating the loss of p53 allele exists in p210(bcr/abl)-expressing hematopoietic cells. Our study presents in vivo evidence that acquired loss of p53 contributes to the blastic transformation of p21(bcr/abl)-expresslng hematopoietic cells and provides insights into the molecular mechanism for blast crisis of human CML.