Impaired DNA replication within progenitor cell pools promotes leukemogenesis.
Impaired DNA replication within progenitor cell pools promotes leukemogenesis.
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DOI：
10.1371/journal.pbio.0030401
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发表时间：
2005-12
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：
Bilousova G;Marusyk A;Porter CC;Cardiff RD;DeGregori J
细胞周期进程受损可能与恶性肿瘤发病率增加相关。通过逆转录病毒转导骨髓祖细胞，然后移植到小鼠体内，我们证明造血祖细胞增殖的抑制会损害竞争，促进祖细胞的扩增，从而获得致癌突变，从而恢复细胞周期进程。损害 DNA 复制的条件会显着增强 Bcr-Abl 或突变体 p53 表达所提供的增殖优势，而在健康复制的条件下，它们不会提供明显的竞争优势。此外，对于 Bcr-Abl 癌基因来说，在 DNA 复制受损的情况下的竞争优势会显着增加白血病的发生。造血祖细胞池内的复制受损可以选择致癌事件，从而促进白血病，这证明了复制能力在预防肿瘤发生中的重要性。复制受损、竞争性差的祖细胞库可以促进肿瘤发生这一事实为肿瘤发生与人类常见的 DNA 复制受损状况（例如膳食叶酸缺乏、针对 dNTP 合成的化疗药物以及对 DNA 代谢重要的基因多态性）之间的联系提供了新的理论依据。作者表明，正常身体细胞的复制能力可以影响携带癌基因的细胞的生长速度，这有助于解释致癌过程中一个鲜为人知的方面。
Impaired cell cycle progression can be paradoxically associated with increased rates of malignancies. Using retroviral transduction of bone marrow progenitors followed by transplantation into mice, we demonstrate that inhibition of hematopoietic progenitor cell proliferation impairs competition, promoting the expansion of progenitors that acquire oncogenic mutations which restore cell cycle progression. Conditions that impair DNA replication dramatically enhance the proliferative advantage provided by the expression of Bcr-Abl or mutant p53, which provide no apparent competitive advantage under conditions of healthy replication. Furthermore, for the Bcr-Abl oncogene the competitive advantage in contexts of impaired DNA replication dramatically increases leukemogenesis. Impaired replication within hematopoietic progenitor cell pools can select for oncogenic events and thereby promote leukemia, demonstrating the importance of replicative competence in the prevention of tumorigenesis. The demonstration that replication-impaired, poorly competitive progenitor cell pools can promote tumorigenesis provides a new rationale for links between tumorigenesis and common human conditions of impaired DNA replication such as dietary folate deficiency, chemotherapeutics targeting dNTP synthesis, and polymorphisms in genes important for DNA metabolism. The authors show that the replicative competence of normal body cells can influence the rate of outgrowth of cells that carry an oncogene, helping explain a poorly understood aspect of carcinogenesis.
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影响因子：
82.9
作者：
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通讯作者：
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