Functional characterization and rational therapeutic targeting of 18q DNA copy number gains in diffuse large B-cell lymphoma

项目摘要 弥漫性大B细胞淋巴瘤（DLBCL）是最常见的淋巴瘤形式，并且常规上是恶性的。 用化疗药物与抗CD20抗体利妥昔单抗的组合治疗。尽管更多 超过一半的患者可以用这种方法治愈，其余的患者预后很差， 生存尽管患者结局存在变异性，但目前没有常规使用的分子生物学方法。 可以用于风险分层或指导特定治疗的生物标志物。也就是说， 目前还没有治疗DLBCL的药物。 我们已经确定了18号染色体q臂（18q）上的一个遗传变异，该变异与一种 DLBCL的侵袭性亚型，并将TCF 4和BCL 2基因定义为该基因座的关键靶标。 BCL 2基因编码一种重要的癌基因，可防止细胞死亡，并可被靶向与 抑制剂维奈托克。TCF 4基因编码一种转录因子蛋白，我们发现它可以驱动 淋巴瘤的关键恶性特性，如促进MYC癌基因的表达和 B细胞受体此外，我们已经定义了一种方法，使用一种新型的免疫抑制剂来消除TCF 4的表达。 针对BET蛋白质的蛋白质降解剂分子。因此，这提供了一个令人兴奋的 合理的治疗途径靶向TCF 4。我们假设，将其与抑制剂结合， BCL 2将靶向由18q改变激活的两个基因，并提供精确的药物 用于治疗这种侵袭性DLBCL亚组的方法。 在这里，我们建议研究DLBCL中18q改变的功能，并验证DLBCL中18q改变的作用。 我们认为这种遗传事件导致淋巴瘤的机制。我们还将进行临床前 BET和BCL 2抑制剂的组合用于18q的特异性治疗靶向的研究 改变。总之，这项工作将促进我们对DLBCL疾病生物学的理解，并可能导致 对这种疾病的精准医疗的进步。

Project Summary Diffuse large B-cell lymphoma (DLBCL) is the most common form lymphoma and is conventionally treated with a combination of chemotherapeutics with the anti-CD20 antibody, Rituximab. Although more than half of patients can be cured with this approach, the remainder have a dire prognosis with a short survival. Despite the variability in patient outcome, there are currently no routinely utilized molecular biomarkers that can be employed for risk stratification or to direct a specific therapy. That is, precision medicine does not currently exist for DLBCL. We have identified a genetic alteration on the q-arm of chromosome 18 (18q) that is associated with an aggressive subtype of DLBCL, and defined the TCF4 and BCL2 genes as critical targets at this locus. The BCL2 gene encodes an important oncogene that prevents cell death, and can be targeted with the inhibitor Venetoclax. The TCF4 gene encodes a transcription factor protein that we have found to drive key malignant properties of lymphoma, such as promoting the expression of the MYC oncogene and the B-cell receptor. In addition, we have defined a way to eliminate TCF4 expression using a novel type of protein-degrader molecules that are directed towards BET proteins. This therefore provides an exciting rational therapeutic avenue for targeting TCF4. We hypothesize that combining this with an inhibitor of BCL2 will target both genes that are activated by 18q alterations, and provide a precision medicine approach for treating this aggressive subset of DLBCL. Here, we are proposing to investigate the function of 18q alterations in DLBCL and validate the mechanism by which we believe this genetic event leads to lymphoma. We will also perform pre-clinical investigation of combinations of BET and BCL2 inhibitors for the specific therapeutic targeting of 18q alterations. Together, this work will advance our understanding of DLBCL disease biology and may lead to advances in precision medicine for this disease.