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

涉及染色体11 q23处MLL基因的非随机相互易位是在急性白血病中检测到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。本文呈现的发现表明MLL融合伴侣AF-4的小结构域与另一MLL融合伴侣AF 9的羧基末端相互作用。AF 4和AF 9的这些部分存在于白血病相关的MLL融合蛋白中，表明AF 4和AF 9能够以其天然形式和/或作为MLL融合蛋白相互作用。MLL-AF_4与AF_9的物理相互作用可能在t（4;11）（q21 ;q23）白血病细胞中起重要作用 婴儿白血病特有的易位我们已经开发了一种小的合成肽，在体外和体内破坏AF 4和AF 9的相互作用。我们证明，肽特异性抑制t（4; 11）白血病细胞系的增殖。对人类健康很重要的是，这种肽-或衍生化合物-可以提供一种治疗婴儿白血病或其他t（4;11）重排白血病患者的独特方法。本研究项目的一个具体目标是描述t（4;11）白血病细胞中肽诱导细胞毒性的机制。我们将检验该肽触发GADD 34蛋白介导的细胞凋亡的假设。实验还将检测t（4;11）白血病细胞中特定下游凋亡途径的激活。接下来，我们将测试这样的预测：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剂的活性。最终，这些研究可能导致开发肽或相关化合物，用于有效治疗ft（4;11）白血病，这是一种众所周知的困难疾病， 婴儿和5-10%的急性淋巴细胞白血病患者。

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 specifically 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 of peptide-induced 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 leukemia.