Poor competition in hematopoietic stem/ progenitor pools favors tumorigenesis

造血干细胞/祖细胞库的不良竞争有利于肿瘤发生

基本信息

批准号：
7452455
负责人：
James V Degregori
金额：
$ 21.45万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-13 至 2010-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Decreased cell cycle progression during hematopoiesis and reduced blood cell production can be associated with increased tumorigenesis, such as in E2F1/E2F2 mutant mice, people with inadequate folate intake, and during particular chemotherapeutic regimens. We propose a hypothesis whereby reduced proliferation of blood progenitors selects for oncogenic mutations that improve cell cycle progression. Basically, impeded proliferation of progenitor cells provides for poor competition, promoting the expansion of progenitors that acquire oncogenic mutations. As cancer development has clear attributes reminiscent of Darwinian evolution, it is perhaps not surprising that it should become easier for a mutant cell clone to be the fittest as the quality of the competition declines. Contexts which involve nucleotide deprivation and DNA damage, and thus impeded DNA replication, often enhance mutation accumulation, and we propose that mutator phenotypes synergize with poor competition to promote tumorigenesis. We suggest that the poorly competitive progenitor environments that result from folate deficiency, particular inherited polymorphisms, and certain chemotherapeutic treatments contribute to increased cancer risk in affected people. To test our hypothesis, we will introduce the oncogenic Bcr-Abl and E2a-Hlf translocation products into mouse BM stem cells using retroviral transduction, and then reconstitute hematopoiesis in recipient mice using these stem cells. We will ask how genetic, dietary and chemotherapeutic contexts that impair cell cycle progression in blood progenitor cells affect the ability of oncogene expressing cells to competitively expand and contribute to leukemogenesis. We will also investigate the mechanism whereby each oncogene improves cell proliferation in compromised progenitors, such as by bypassing checkpoints and restoring DNA synthesis. We anticipate that particular conditions that impair S phase progression will promote the expansion and tumorigenicity of oncogene expressing progenitor cells. These studies should define novel factors governing tumorigenesis, and will create unique model systems that could suggest further epidemiological studies in humans.

描述（由申请人提供）：造血过程中细胞周期进程的减少和血细胞产生的减少可能与肿瘤发生的增加有关，例如在 E2F1/E2F2 突变小鼠、叶酸摄入不足的人以及特定化疗方案期间。我们提出了一个假设，即血液祖细胞增殖的减少选择了改善细胞周期进程的致癌突变。基本上，祖细胞增殖受阻会导致竞争不良，从而促进获得致癌突变的祖细胞的扩增。由于癌症的发展具有让人想起达尔文进化论的明显属性，因此随着竞争质量的下降，突变细胞克隆变得更容易成为最适者，这也许并不奇怪。涉及核苷酸剥夺和 DNA 损伤的背景，从而阻碍 DNA 复制，通常会增强突变积累，我们认为突变体表型与不良竞争协同作用，促进肿瘤发生。我们认为，叶酸缺乏、特别是遗传性多态性和某些化疗治疗导致的竞争性较差的祖细胞环境会导致受影响人群的癌症风险增加。为了检验我们的假设，我们将使用逆转录病毒转导将致癌的 Bcr-Abl 和 E2a-Hlf 易位产物引入小鼠 BM 干细胞中，然后使用这些干细胞在受体小鼠中重建造血功能。我们将询问损害血液祖细胞细胞周期进程的遗传、饮食和化疗环境如何影响癌基因表达细胞竞争性扩增和促进白血病发生的能力。我们还将研究每种癌基因改善受损祖细胞增殖的机制，例如通过绕过检查点和恢复 DNA 合成。我们预计损害 S 期进展的特定条件将促进表达癌基因的祖细胞的扩增和致瘤性。这些研究应该定义控制肿瘤发生的新因素，并将创建独特的模型系统，为人类进一步的流行病学研究提供建议。