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 Blood, 1 December 2008, Vol. 112, No. 12, pp. 4690-4693.
Prepublished online as a Blood First Edition Paper on September 16, 2008; DOI 10.1182/blood-2008-01-134056.

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NEOPLASIA

Brief Report

The PHD fingers of MLL block MLL fusion protein–mediated transformation

Andrew G. Muntean1, Diane Giannola1, Aaron M. Udager2, and Jay L. Hess1

Departments of1 Pathology and 2 Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor

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 1 of more than 60 different translocation partners. The translocations consistently delete the plant homeodomain (PHD) fingers 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 2 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.


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