Molecular Pathogenesis of AF10-Rearranged Leukemias

项目总结 在过去的几年里，在分子变化的表征方面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 参与儿童癌症特定亚型的研究已经确定。然而，尽管有这些令人印象深刻的 对于大多数儿童癌症，缺乏安全有效的治疗方法。白血病是主要原因 儿童癌症相关死亡率和许多儿童白血病，可以选择性地消除 几乎没有不良副作用的癌细胞一直难以捉摸。因此，有一个紧急的临床未得到满足的问题 需要为儿童白血病开发无毒和有针对性的治疗方法。 我们的建议集中在AF10基因重排的白血病上。这些重新安排是 在急性髓系白血病(AML)、T细胞性急性淋巴细胞白血病(T-ALL)等亚型中观察到 儿童和成人的白血病。AF10重排(AF10-R)白血病可以被认为是典型模型 在儿童癌症中，嵌合融合癌蛋白或改变的转录因子驱动广泛的自我- 癌细胞的更新和分化受损。我们最近对1,000多名儿童AML的数据进行了分析 患者证明AF10基因融合比通常认为的要常见得多(代表 6.5%的儿童急性髓系白血病)，并构成对初级治疗耐药的最高风险群体之一 和复发率。我们详细的机制研究表明，AF10融合蛋白CAMAL-AF10 激活许多与干细胞自我更新和炎症信号有关的通路，其中许多是 与急性髓系白血病预后不良独立相关。在这个方案中，我们将使用一系列的正交化 方法学，包括蛋白质组，基因组，表观基因组和详细的机制研究在人类和 小鼠AML模型，以确定Calm-AF10融合蛋白如何导致白血病发生。 拟议目标的成功执行将推动我们朝着寻找更新的靶向疗法的努力 用于AF10-R AML，具有较少的有害毒性。我们的研究结果也有可能显著地 影响由相关机制驱动的其他几种儿童白血病的治疗策略。

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.