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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 涉及染色体11q23上MLL基因的非随机相互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。本研究的结果表明，MLL融合伙伴AF-4的一个小结构域与另一个MLL融合伙伴AF9的羧基末端相互作用。AF4和AF9的这些部分存在于白血病相关的MLL融合蛋白中，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婴儿白血病t(4；11)(q21；q23)易位细胞的发生中起重要作用。我们已经开发了一种小的合成多肽，它可以在体外和体内破坏AF4和AF9的相互作用。我们证明该多肽能显著抑制t(4；11)白血病细胞系的增殖。这种多肽或衍生化合物对人类健康很重要，可以提供一种独特的方法来治疗t(4；11)重排的婴儿白血病或其他白血病患者。本研究项目的一个具体目标是研究多肽对t(4；11)白血病细胞的细胞毒作用的机制。我们将检验这一假设，即该肽通过Gadd34蛋白介导的细胞凋亡。实验还将检查t(4；11)白血病细胞中特定下游凋亡通路的激活情况。接下来，我们将测试这一预测，即通过敏化t(4；11)白血病细胞的凋亡，该肽将显著增强传统化疗药物的活性。最终，这些研究可能导致有效治疗(4；11)白血病的多肽或相关化合物的开发。(4；11)白血病是一种臭名昭著的疑难疾病，影响着大多数婴儿和5%-10%的急性淋巴细胞白血病患者。

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 leukemia.