PROJECT 9: STEM CELL FUNCTION & GENOME INSTABILITY IN LYMPHOMYELOID NEOPLASIA

项目 9：干细胞功能

• 批准号: 7720707
• 负责人: KEVIN D MILLS
• 金额: $ 28.9万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-04 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720707
• 关键词: Arts; B-Lymphocytes; Bone Marrow; Cancer Biology; Cell physiology; Chromosomal Instability; Computer Retrieval of Information on Scientific Projects Database; DNA Double Strand Break; Data; Double Strand Break Repair; Exhibits; Funding; Genomic Instability; Grant; Hematopoietic stem cells; Homeostasis; Institution; Lymphoid; Lymphoma; Lymphomagenesis; Malignant - descriptor; Malignant Neoplasms; Mesenchymal Stem Cells; Mus; Neoplasms; Normal tissue morphology; Numbers; Pathway interactions; Predisposition; Research; Research Personnel; Resistance; Resources; S-Phase Fraction; Source; Stem cells; Stress; Stromal Cells; Testing; Tissues; United States National Institutes of Health; cellular targeting; fitness; mouse model; prevent; progenitor; sarcoma; stem; tumor; tumorigenesis

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Accumulating evidence implicates the corruption of normal, tissue-specific stem cell function or homeostasis in multiple aspects of cancer biology. Moreover, cancer-associated stem and progenitor cells have been identified in a number of cancers. However, questions remain regarding the origin of cancer-specific stem cells, their relationship to normal stem cells, and the importance of stem cell microenvironments for modulating malignant transformation. One hallmark of many tumors is chromosome instability, but the mechanisms of instability, and the relevant cellular targets, remain mostly unidentified. We have previously shown that the nonhomologous end joining (NHEJ) pathway of DNA double-strand break repair suppresses tumorigenesis in numerous tissues of either hematopoietic stem cell (HSC) or bone marrow stromal/mesenchymal stem cell (MSC) origin. In this context, we hypothesize that the NHEJ pathway is critical for the fitness and function of normal HSC and MSC, preventing their malignant transformation. Using a mouse model of NHEJ deficiency, prone to pro-B lymphomagenesis, we have made significant progress in testing these hypotheses. We have now obtained data indicating that NHEJ-deficient bone marrow stromal cells (the hematopoietic stem cell microenvironment) exhibit a higher mitotic index and overall greater stress resistance than their wild-type counterparts. This surprising finding may explain the predisposition of Art-null (Trp53 heterozygous) mice to develop apparently MSC-derived anaplastic sarcomas. Moreover, these data may point to critical interactions between NHEJ-defective lymphoid progenitors and their bone marrow stromal microenvironment, that may be relevant to lymphoma initiation. Next, we will assess whether NHEJ-deficient MSCs exhibit chromosomal instability or modulate pro-B cell lymphomagenesis.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 越来越多的证据表明，在癌症生物学的多个方面，正常的、组织特异性的干细胞功能或动态平衡遭到破坏。此外，在一些癌症中已经发现了与癌症相关的干细胞和祖细胞。然而，关于癌症特异性干细胞的起源、它们与正常干细胞的关系以及干细胞微环境对调节恶性转化的重要性等问题仍然存在。许多肿瘤的一个特点是染色体不稳定，但不稳定的机制和相关的细胞靶点大多仍未确定。我们先前已经证明，DNA双链断裂修复的非同源末端连接(NHEJ)途径抑制了大量造血干细胞(HSC)或骨髓基质/间充质干细胞(MSC)来源的组织中的肿瘤发生。在此背景下，我们假设NHEJ通路对于正常的HSC和MSC的适合性和功能至关重要，从而防止它们的恶变。利用NHEJ缺乏症的小鼠模型，我们在检验这些假说方面取得了重大进展。我们现在已经获得的数据表明，NHEJ缺陷的骨髓基质细胞(造血干细胞微环境)比它们的野生型具有更高的有丝分裂指数和更强的抗逆性。这一令人惊讶的发现可能解释了Art基因缺失(Trp53杂合子)小鼠患上明显由MSC来源的间变性肉瘤的倾向。此外，这些数据可能指向NHEJ缺陷的淋巴祖细胞与其骨髓基质微环境之间的关键相互作用，这可能与淋巴瘤的发生有关。接下来，我们将评估NHEJ缺陷的MSCs是否表现出染色体不稳定或调节前B细胞淋巴肿大。