Submitted January 15, 2008
Accepted August 13, 2008
The PHD fingers of MLL block MLL fusion protein-mediated transformation
Andrew G. Muntean, Diane Giannola, Aaron M. Udager, and Jay L. Hess*
Department of Pathology, The University of Michigan Medical School, Ann Arbor, MI, United States
Department of Cell and Developmental Biology, The University of Michigan Medical School, Ann Arbor, MI, United States
* Corresponding author; email: jayhess{at}umich.edu.
Chromosomal translocations involving the mixed lineage leukemia (MLL) gene are associated with aggressive acute lymphoid and myeloid leukemias. These translocations are restricted to an 8.3 kb breakpoint region resulting in fusion of amino terminal MLL sequences in frame to one of more than 60 different translocation partners. The translocations consistently delete the plant homeodomain domain (PHD) and more carboxyl terminal MLL sequences. The function of the PHD fingers is obscure and their specific role in transformation has not been explored. Here we show that inclusion of the PHD fingers in the MLL fusion protein MLL-AF9 blocked immortalization of hematopoietic progenitors. Inclusion of two or more PHD fingers reduced association with the Hoxa9 locus and suppressed Hoxa9 up regulation in hematopoietic progenitors. These data provide an explanation for why MLL translocation breakpoints exclude the PHD fingers and suggest a possible role for these domains in regulating the function of wild-type MLL.
