TULANE CANCER GENETICS COBRE: INOVATIVE THERAPIES FOR T(4;11) LEUKEMIA

杜兰大学癌症遗传学 COBRE：T(4;11) 白血病的创新疗法

• 批准号: 7382136
• 负责人: Charles Stanley Hemenway
• 金额: $ 8.63万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382136
• 关键词: TULANE; CANCER; GENETICS; COBRE; INOVATIVE

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. Non-random reciprocal translocations involving the MLL gene at chromosome 11 q23 are among the most common chromosome abnormalities detected in acute leukemia. Importantly, these reciprocal translocations result in the expression of chimeric MLL fusion genes. Findings presented herein indicate that a small domain of the MLL fusion partner AF-4 interacts with the carboxy-terminus of another MLL fusion partner AF9.These portions of AF4 and AF9 are present in leukemia-associated MLL fusion proteins suggesting that AF4 and AF9 are capable of interacting in their native form and/or as MLL fusion proteins. The physical interaction of MLL-AF4 with AF9 may be important in leukemogenesis in cell with t(4;11)(q21 ;q23) translocations characteristic of infant leukemia. We have developed a small synthetic paptide that disrupts the interaction of AF4 and AF9 in vitro and in vivo. We demonstrate that the peptide spe''''_ifically inhibits the proliferation of t(4; 11) leukemia cell lines. Important to human health, this peptide- or derivative compounds- could provide a unique means of treating patients with infant leukemia or other leukemias with t(4;11) rearrangements. A specific goal of this research project is to characterize the mechanism ofpeptideinduced cytotoxicity in t(4;11) leukemia cells. We will test the hypothesis that the peptide triggers apoptosis mediated by the GADD34 protein. Experiments will also examine the activation of specific downstream apoptotic pathways in t(4;11) leukemia cells. Next, we will test the prediction that, by sensitizing t(4;11) leukemia cells to apoptosis, the peptide will significantly enhance the activity of conventional chemotherapeutic agents. Ultimately, these studies may lead to the development ofpeptides or related compounds for the effective treatment oft(4;11) leukemia, a notoriously difficult disease that affects most babies and 5-10% of all people with acute lymphoblastic leukemi

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。涉及染色体11q23上MLL基因的非随机反向易位是在急性白血病中发现的最常见的染色体异常。重要的是，这些相互易位导致嵌合MLL融合基因的表达。本文的研究结果表明，MLL融合伙伴AF-4的一个小区域与另一个MLL融合伙伴AF9的羧基端相互作用。AF4和AF9的这些部分存在于白血病相关的MLL融合蛋白中，这表明AF4和AF9能够以其天然形式和/或作为MLL融合蛋白相互作用。MLL-AF4与AF9的物理相互作用可能在具有婴儿白血病特征性t(4;11)（q21;q23）易位的细胞的白血病发生中起重要作用。我们已经开发出一种小的合成肽，在体外和体内破坏AF4和AF9的相互作用。我们证明肽spe''‘’有效地抑制t（4; 11）白血病细胞系的增殖。对人类健康至关重要的是，这种肽或衍生物化合物可以为治疗婴儿白血病或其他t（4;11）重排白血病患者提供一种独特的方法。本研究项目的一个具体目标是表征肽诱导t（4;11）白血病细胞毒性的机制。我们将验证该肽触发GADD34蛋白介导的细胞凋亡的假设。实验还将研究t（4;11）白血病细胞中特定下游凋亡通路的激活。接下来，我们将验证这一预测，即通过使t（4;11）白血病细胞对凋亡敏感，该肽将显著增强常规化疗药物的活性。最终，这些研究可能会导致多肽或相关化合物的开发，以有效治疗白血病（4;11），白血病是一种众所周知的困难疾病，影响大多数婴儿和5-10%的急性淋巴细胞白血病患者