Acute lymphocytic leukemia (ALL) is a rapidly progressive, life-threatening disease for which certain molecular markers are strongly predictive of poor clinical outcome. One such marker involves reciprocal chromosomal translocations of the mixed-lineage leukemia (MLL) gene at locus 11q23. In over 80% of infant ALL cases, translocations at 11q23 result in the production of a functional chimeric protein consisting of the N-terminal portion of MLL fused to the C- terminal portion of more than 60 fusion partners. The impressive heterogeneity among fusion partners raises difficult questions as to how MLL fusion proteins cause leukemia. It is hypothesized that MLL-mediated leukomogenesis depends upon protein interactions specific for the C-terminal fusion partner, and that these protein interactions serve as potential therapeutic molecular targets. This proposal focuses on identifying protein interactions capable of interacting with the one of the common fusion proteins, MLL-AF9, validating the necessity for these interactions in hematopoietic stem cell transformation, and enhancing the therapeutic potential of a molecularly-targeted chemotherapeutic developed and characterized in our lab through screening of a combinatorial peptide library. The data from these experiments will enhance our understanding of the underlying mechanism of MLL-mediated leukemogenesis, identify novel therapeutic targets, and aid in the development of more effective treatments designed to target the abnormal activity of the MLL-chimeric protein. ? ? ? ?
| Palermo, Christine M; Bennett, Cecily A; Winters, Amanda C et al. (2008) The AF4-mimetic peptide, PFWT, induces necrotic cell death in MV4-11 leukemia cells. Leuk Res 32:633-42 |
