) Acute lymphoblastic leukemias that bear chromosomal translocations at 11q23 possess rearrangements of the Mixed Lineage Leukemia gene (MLL, HRX, ALL-1) and have a poor prognosis. Both infant leukemia and secondary leukemias following therapy with DNA topoisomerase II inhibitors frequently bear MLL translocations. This project will utilize genetic models and RNA profiling to determine the function and the critical target genes of both Mll and the Mll-fusions. A series of selected loss-of-function models of Mll in distinct hematopoietic lineages will reveal the normal developmental roles of Mll, enable the profiling of Hox expression and discover additional targets using DNA microarray technology. The Hoxc8 locus, which is reciprocally regulated by Mll of the Tr-G and Bmi-1 of the Pc-G families, will provide the proper chromatin context to assess MLL domains and an MLL multimeric protein complex. We will pursue MLL-CBP as a model MLL-fusion protein as we have also noted an MLL/CBP physical interaction and a role for acetylation in regulating MLL target genes. Finally, in collaboration with Todd Golub, we will compare the RNA profile of drug-sensitive MLL-leukemias at presentation versus drug-resistant MLL-leukemias at early relapse in an attempt to identify a drug-resistance gene program.
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