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

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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.