Irradiation selects for p53-deficient hematopoietic progenitors.
Irradiation selects for p53-deficient hematopoietic progenitors.
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DOI：
10.1371/journal.pbio.1000324
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发表时间：
2010-03-02
期刊：
影响因子：
9.8
通讯作者：
DeGregori J
中科院分区：
文献类型：
--
作者：
Marusyk A;Porter CC;Zaberezhnyy V;DeGregori J
虽然在非应激造血中，p53的破坏是选择性中性的，但在辐射后，它具有很强的选择性优势，导致p53突变克隆的扩张和淋巴瘤的发展。识别和表征驱动癌症进化的突变是癌症研究的主要重点。因此，显性范式将一般致癌物和电离辐射的致癌作用归因于它们对编码癌基因和抑癌基因的遗传位点的直接诱变作用。然而，辐射的影响并不局限于编码癌基因和抑癌基因的遗传位点，因为辐射诱导了细胞及其微环境中的许多其他变化，这些变化可能潜在地影响某些癌基因突变的选择性效应。P53是一种关键的肿瘤抑制因子，它的缺失可以抵抗包括辐射在内的多种遗传毒性刺激。考虑到p53基因缺失的动物发展为高外显率的T细胞淋巴瘤，以及辐射显著加速了p53杂合子小鼠的淋巴瘤发展，我们假设增加对p53基因缺失细胞的选择有助于辐射和诱导淋巴系统恶性肿瘤之间的因果联系。我们试图通过小鼠模型来确定电离辐射是否选择体内p53缺陷的造血祖细胞。我们发现，在没有应激反应的造血系统中，或在先前照射过的允许从照射中恢复的骨髓中，P53的破坏并不提供明显的选择性优势。相比之下，在照射后，破坏p53提供了显著的选择性优势，导致p53缺陷克隆的长期扩张，并增加了淋巴瘤的发展。P53基因突变的细胞的选择似乎归因于几个因素：保护免受急性辐射诱导的祖细胞的消融，防止辐射导致干细胞和祖细胞克隆形成能力的丧失，改善祖细胞适合性的长期维持，以及禁用/消除竞争的p53野生型祖细胞。这些研究表明，电离辐射的致癌作用可以部分解释为增加了对带有p53破坏的细胞的选择，这保护了祖细胞不会立即消除，也不会在辐射后长期降低适合性。癌症的进展可以通过达尔文进化论的框架来理解，这一框架涉及两个主要因素：基因突变和选择。随机突变被认为导致肿瘤的起始和表型多样化，环境影响中介选择那些增加肿瘤细胞适合性的突变。由于癌基因突变是自发恶性肿瘤发展所必需的，而且这些突变的实验性引入通常会导致转化和癌症，致癌物导致癌症的原因传统上被归因于它们诱导新的致癌突变。取而代之的是，我们通过检测关键的肿瘤抑制基因p53失活的选择效应，询问了电离辐射是否影响致癌突变的选择。虽然在非应激造血祖细胞群体中，p53的破坏是选择性中性的，但它在辐射后提供了强大的选择性优势。选择P53缺陷克隆是由于对辐射诱导的细胞死亡和细胞适合性丧失的保护。重要的是，在非辐射野生型竞争者存在的情况下，携带p53破坏的辐射后细胞的选择性扩张被阻止，这表明通过辐射使竞争野生型细胞失效对于选择p53缺失细胞是至关重要的。我们的结果认为，辐射诱导癌症涉及到对具有辐射抗性的突变的选择，并表明在理解、预防和治疗癌症时，有必要更多地关注致癌环境对选择的影响。
While disruption of p53 is selectively neutral within non-stressed hematopoiesis, it confers a strong selective advantage upon irradiation, leading to expansion of p53 mutant clones and lymphoma development. Identification and characterization of mutations that drive cancer evolution constitute a major focus of cancer research. Consequently, dominant paradigms attribute the tumorigenic effects of carcinogens in general and ionizing radiation in particular to their direct mutagenic action on genetic loci encoding oncogenes and tumor suppressor genes. However, the effects of irradiation are not limited to genetic loci that encode oncogenes and tumor suppressors, as irradiation induces a multitude of other changes both in the cells and their microenvironment which could potentially affect the selective effects of some oncogenic mutations. P53 is a key tumor suppressor, the loss of which can provide resistance to multiple genotoxic stimuli, including irradiation. Given that p53 null animals develop T-cell lymphomas with high penetrance and that irradiation dramatically accelerates lymphoma development in p53 heterozygous mice, we hypothesized that increased selection for p53-deficient cells contributes to the causal link between irradiation and induction of lymphoid malignancies. We sought to determine whether ionizing irradiation selects for p53-deficient hematopoietic progenitors in vivo using mouse models. We found that p53 disruption does not provide a clear selective advantage within an unstressed hematopoietic system or in previously irradiated BM allowed to recover from irradiation. In contrast, upon irradiation p53 disruption confers a dramatic selective advantage, leading to long-term expansion of p53-deficient clones and to increased lymphoma development. Selection for cells with disrupted p53 appears to be attributable to several factors: protection from acute irradiation-induced ablation of progenitor cells, prevention of irradiation-induced loss of clonogenic capacity for stem and progenitor cells, improved long-term maintenance of progenitor cell fitness, and the disabling/elimination of competing p53 wild-type progenitors. These studies indicate that the carcinogenic effect of ionizing irradiation can in part be explained by increased selection for cells with p53 disruption, which protects progenitor cells both from immediate elimination and from long-term reductions in fitness following irradiation. Cancer progression can be understood through the framework of Darwinian evolution, which involves two major factors: genetic mutation and selection. Random mutations are thought to result in the initiation and phenotypic diversification of tumors, and environmental influences mediate selection for those mutations that increase tumor cell fitness. Since oncogenic mutations are necessary for the development of spontaneous malignancies and since experimental introduction of these mutations often leads to transformation and cancers, the causation of cancers by carcinogens is traditionally attributed to their induction of new mutations that are oncogenic. We instead asked whether selection for oncogenic mutations is affected by ionizing irradiation, an archetypal mutagenic carcinogen, by examining the selective effects of inactivation of the critical tumor suppressor gene p53. While disruption of p53 is selectively neutral in populations of unstressed hematopoietic progenitors, it provides a strong selective advantage upon irradiation. This selection of p53-deficient clones is attributable to protection from irradiation-induced cell death and loss of cellular fitness. Importantly, the selective expansion of irradiated cells bearing p53 disruption is blocked in the presence of non-irradiated wild-type competitors, indicating that the disabling of competing wild-type cells by irradiation is critical for selection of p53-deficient cells. Our results argue that induction of cancers by irradiation involves selection for mutations that confer radioresistance, and suggest that greater focus on how carcinogenic contexts impact on selection is warranted in understanding, preventing and treating cancers.
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影响因子：
9.8
作者：
Bilousova G;Marusyk A;Porter CC;Cardiff RD;DeGregori J
通讯作者：
DeGregori J
影响因子：
64.8
作者：
DONEHOWER, LA;HARVEY, M;BRADLEY, A
通讯作者：
BRADLEY, A
影响因子：
64.8
作者：
Lowe, SW;Cepero, E;Evan, G
通讯作者：
Evan, G
影响因子：
78.5
作者：
Brown, JM;Attardi, LD
通讯作者：
Attardi, LD
DOI：
10.1073/pnas.90.12.5742
发表时间：
1993-06-15
影响因子：
11.1
作者：
LEE, JM;BERNSTEIN, A
通讯作者：
BERNSTEIN, A