V(D)J RECOMBINASE & CHROMOSOME TRANSLOCATION IN LYMPHOMA

淋巴瘤是人类发病率和死亡率的重要原因。虽然参与淋巴瘤形成的原癌基因已经被确定，但导致淋巴瘤的完整遗传路径仍然难以捉摸。人们注意到大多数人类淋巴瘤都有染色体易位，其中大多数涉及免疫球蛋白(Ig)基因。有证据表明，V(D)J重组代表了一种受调控的遗传不稳定形式，可能介导了染色体易位，导致影响淋巴细胞生长或存活的基因表达失控。淋巴瘤性事件是罕见的，这一事实强调了细胞机制的存在，以防止异常的V(D)J重组。具有SCID基因突变的小鼠在有效修复编码端以产生功能性抗原受体的能力方面受到严重限制，并且具有缺陷的双链DNA断裂修复，表明SCID基因产物在V(D)J重组和双链DNA断裂修复中发挥作用。SCID x P53-/-小鼠均匀地发展为播散性B细胞淋巴瘤，我们发现这种淋巴瘤含有复发的t(12；15)，涉及IgH基因。因此，我们定义了一条导致特定染色体易位的遗传途径，可能涉及V(D)J重组酶机制。我们建议使用FISH分析来定位和克隆12号染色体易位断裂点，检查序列中V(D)J重组的特征，并确定潜在的癌基因。利用小鼠模型，我们建议研究V(D)J重组缺失是否抑制侵袭性前B细胞淋巴瘤的发展。这个项目的长期目标将是研究V(D)J重组作为导致淋巴瘤发展的染色体易位的潜在遗传途径的作用。这种洞察力可能会加深对淋巴肿大的理解，并可能有助于开发新的抗肿瘤策略。

Lymphomas are a significant cause of morbidity and mortality in humans. Whereas protooncogenes involved in lymphoma formation have been identified, the complete genetic pathways resulting in lymphomas remain elusive. The majority of human lymphomas have been noted to have chromosomal translocations, and most of these involve the immunoglobulin (Ig) loci. Evidence suggests that V(D)J recombination, which represents a regulated form of genetic instability, may mediate chromosomal translocations resulting in the deregulated expression of genes affecting lymphocyte growth or survival. The fact that lymphomagenic events are rare underscores the existence of cellular mechanisms to prevent aberrant V(D)J recombination. Mice with mutations in the SCID gene are severely limited in their ability to effectively repair coding ends to generate functional antigen receptors and have defective double strand DNA break repair, indicating that the SCID gene product plays a role in both V(D)J recombination and double strand DNA break repair. SCID x p53 -/- mice uniformly develop disseminated B cell lymphomas, which we have discovered contain recurrent t(12;15) involving the IgH locus. We have, thus, defined a genetic pathway leading to a particular chromosomal translocation, possibly involving the V(D)J recombinase mechanism. We propose to use FISH analysis to map and clone the chromosome 12 translocation breakpoint, examining the sequence for characteristics of V(D)J recombination and identifying potential oncogenes. Using a mouse model, we propose to investigate whether absence of V(D)J recombination suppresses the development of aggressive pro-B cell lymphomas. The long term goal of this project will be to study the role of V(D)J recombination as a potential genetic pathway for chromosomal translocations leading to the development of lymphomas. Such insight may further the understanding of lymphomagenesis and may help in the development of novel anti-tumor strategies.