Molecular Pathogenesis of AF10-Rearranged Leukemias

项目摘要 在过去的几年里，在表征细胞中的分子改变方面已经取得了相当大的进展。 儿童癌症。许多定义基因组异常以及转录和信号网络 参与儿科癌症的特定亚型。尽管这些令人印象深刻的 然而，由于缺乏先进技术，大多数儿童癌症缺乏安全有效的治疗方法。白血病是导致 儿童和许多儿童白血病的癌症相关死亡率， 几乎没有不希望的副作用的癌细胞一直是难以捉摸的。因此，有一个迫切的临床未满足的 需要为儿童白血病开发无毒的靶向治疗方法。 我们的建议是集中在白血病与AF 10基因重排。这些重新安排是 在急性髓性白血病（AML）、T细胞急性淋巴细胞白血病（T-ALL）和其他亚型的白血病中观察到， 儿童和成人的白血病。AF 10重排（AF 10-R）白血病可视为原型模型 嵌合融合癌蛋白或改变的转录因子驱动广泛的自身免疫反应的儿科癌症， 更新和癌细胞分化受损。我们最近分析了1,000多名儿童AML患者的数据， 患者表明，AF 10基因融合比通常认识到的要常见得多（代表 6.5%的儿童AML），构成了对主要治疗耐药的最高风险组之一 和复发率。我们详细的机制研究表明，AF 10融合蛋白CALM-AF 10 激活了许多与干细胞自我更新和炎症信号相关的途径，其中许多是 与AML的不良结局独立相关。在这个建议中，我们将使用一系列正交 方法，包括蛋白质组学，基因组学，表观基因组学和详细的机制研究，在人类和 小鼠AML模型，以确定CALM-AF 10融合蛋白如何引起白血病发生。 成功实现这些目标将推动我们寻找新的靶向治疗方法的努力 对于AF 10-R AML，具有更少的不希望的毒性。我们的研究结果也有可能显着 影响由相关机制驱动的其他几种儿科白血病亚型的治疗策略。

PROJECT SUMMARY There has been considerable progress in the last few years in the characterization of molecular alterations in childhood cancer. Many defining genomic abnormalities as well as transcriptional and signaling networks involved in specific sub-types of pediatric cancers have been identified. However, despite these impressive advances, safe and effective therapies for most pediatric cancers are lacking. Leukemias are the leading cause of cancer-linked mortality in children and for many pediatric leukemias, therapies that can selectively eliminate cancer cells with few undesirable side effects have been elusive. Therefore, there is an urgent clinically unmet need to develop non-toxic and targeted therapies for pediatric leukemia. Our proposal is focused on leukemias with rearrangements of the AF10 gene. These rearrangements are observed in acute myeloid leukemia (AML), T-cell acute lymphoblastic leukemia (T-ALL) and other sub-types of leukemia in children and adults. AF10-rearranged (AF10-R) leukemias can be considered prototypical models of pediatric cancers in which chimeric fusion oncoproteins or altered transcription factors drive extensive self- renewal and impaired differentiation of cancer cells. Our recent analysis of data from over 1,000 pediatric AML patients demonstrates that AF10 gene fusions are much more common than generally appreciated (representing 6.5% of pediatric AML) and constitute one of the highest risk-groups in terms of resistance to primary therapies and relapse rates. Our detailed mechanistic studies demonstrate that the AF10 fusion protein CALM-AF10 activates a number of pathways linked to stem cell self-renewal and inflammatory signaling, many of which are independently associated with poor outcomes in AML. In this proposal, we will use a series of orthogonal methodologies, including proteomic, genomic, epigenomic and detailed mechanistic studies in both human and mouse AML models, to determine how the CALM-AF10 fusion protein causes leukemogenesis. The successful execution of the proposed aims will advance our efforts towards finding newer targeted therapies for AF10-R AML with fewer unwanted toxicities. Results from our studies also have the potential to significantly influence treatment strategies in several other sub-types of pediatric leukemias driven by related mechanisms.