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

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 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稳态的破坏。 此外，癌症相关的干细胞和祖细胞已经在许多癌症中被鉴定。 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，仍然存在问题。 许多肿瘤的一个标志是染色体不稳定性，但不稳定性的机制和相关的细胞靶点大多尚未确定。 我们以前已经表明，DNA双链断裂修复的非同源末端连接（NHEJ）途径抑制造血干细胞（HSC）或骨髓基质/间充质干细胞（MSC）来源的许多组织中的肿瘤发生。 在这种情况下，我们假设NHEJ通路对正常HSC和MSC的适应性和功能至关重要，可以防止它们的恶性转化。使用NHEJ缺乏症的小鼠模型，倾向于pro-B淋巴瘤，我们在测试这些假设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）表现出更高的有丝分裂指数和整体更大的抗应激能力比野生型。 这一令人惊讶的发现可能解释了Art-null（Trp 53杂合）小鼠发生明显MSC源性间变性肉瘤的倾向。此外，这些数据可能指向NHEJ缺陷型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MSC是否表现出染色体不稳定性或调节前B细胞淋巴瘤发生。

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.