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

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。一种新兴的癌症观点认为，正常干细胞的腐败可能有助于肿瘤的形成，进展或治疗抗性。事实上，在一些肿瘤中已经鉴定出癌症干细胞，但在大多数情况下，这些细胞虽然被假定，但尚未被鉴定或表征。了解癌症的重要挑战将是识别癌症干细胞，确定它们与正常干细胞的关系，并评估来自不同恶性肿瘤的癌症干细胞是否表现出共同的特征。癌症的另一个标志是染色体不稳定。虽然特征性染色体异常已被记录为许多癌症，并且通常具有临床预测价值，但其起源仍不清楚。干细胞生物学和染色体不稳定性都是与癌症的临床管理有关的重要（并且可能相关）问题，因此，本提案的目的是确定正常干细胞特性的紊乱是否与淋巴瘤形成相关，并确定染色体不稳定性背后的机制，特别是在正常或癌症干细胞中。为了实现这些目标，我们正在利用里希特综合征的小鼠模型，里希特综合征是一种导致慢性白血病转化为急性侵袭性淋巴瘤的疾病，与治疗抗性和快速临床恶化相关。在这种小鼠模型中，DNA修复缺陷产生染色体不稳定性，导致形成具有特征性染色体重排的淋巴瘤。利用该系统，我们将识别和表征癌症干细胞群体，并确定驱动染色体不稳定性的分子机制。这项工作对于开发改进的诊断方法和新的癌症治疗方法非常重要。

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. An emerging view of cancer suggests that corruption of normal stem cells can contribute to tumor formation, progression, or therapy resistance. Indeed cancer stem cells have been identified in some tumors, but in most cases such cells, while postulated, have not yet been identified or characterized. Important challenges in understanding cancer will be to identify cancer stem cells, to determine their relationship to normal stem cells, and to evaluate whether cancer stem cells from different malignancies exhibit common characteristics. Another hallmark of cancer is chromosome instability. While characteristic chromosome abnormalities have been documented for numerous cancers, and are often of clinically predictive value, their origin remains unclear. Both stem cell biology and chromosome instability are important (and likely related) issues pertaining to clinical management of cancer, Therefore, the objectives of this proposal are to determine whether derangement of normal stem cell properties is related to lymphoma formation, and to identify the mechanisms behind chromosome instability, especially in normal or cancer stem cells. To achieve these objectives we are exploiting a mouse model of Richter¿s syndrome, a disease leading to conversion of chronic leukemia to acute, aggressive lymphoma associated with therapy resistance and rapid clinical deterioration. In this mouse model, DNA repair deficiency produces chromosome instability, leading to formation of lymphomas with characteristic chromosomal rearrangements. With this system we will identify and characterize the cancer stem cell population, and determine the molecular mechanisms driving chromosome instability. This work will be important for developing improved diagnostic methods and novel cancer therapies.