Rearrangements of the mixed lineage leukemia gene (MLL), the human homologue of the Drosophila gene Trithorax (trx), are associated with aggressive lymphoid and myeloid leukemias in both children and adults. Fusion of MLL to one of over 25 different translocation partners converts it into a leukemogenic oncoprotein. In addition internal tandem duplications of MLL occur in about 10% of acute myeloid leukemias with normal cytogenetics and are associated with a poor prognosis. A rapidly growing body of evidence suggests that MLL fusion proteins transform via increased expression of Hox genes, including Hox a9, which in cooperation with the Hox cofactor Meis1, promote leukemogenesis. Our studies of wild-type MLL indicate that it is a histone methyltransferase that dynamically regulates Hox gene expression. MLL binds directly to Hox promoters resulting in both histone acetylation and histone H3 lysine 4 methylation. MLL fusion proteins also upregulate expression of Hox genes and Meis1, which is likely the mechanism by which these proteins cause leukemia. These findings provide a strong rationale and experimental framework for defining how leukemogenic forms of MLL modify the histone code to deregulate Hox gene expression. In SA#1 we will define how wild-type MLL fusion modifies the """"""""histone code"""""""" at target Hox genes, and determine how this code is differentially altered by MLL fusion proteins in hematopoietic cells. In SA#2 we examine how targeting of MLL to Hox promoters results in increased histone acetylation. Specifically we will determine if MLL affects recruitment of histone deacetylase containing corepressor complexes to target promoters and explore the role of a highly conserved domain of MLL in this process. In SA#3 we will examine whether coregulator recruitment changes during the downregulation of Hox a9 expression that occurs during myeloid differentiation and how this process may be perturbed by leukemogenic forms of MLL. These experiments will provide fundamental insights into mechanisms of transcriptional regulation by MLL and may facilitate the development of targeted therapies for acute leukemias with MLL rearrangements.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA078815-10
Application #
7125018
Study Section
Special Emphasis Panel (ZRG1-MEP (05))
Program Officer
Mufson, R Allan
Project Start
1998-07-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
10
Fiscal Year
2006
Total Cost
$292,598
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pathology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Fisher, C L; Lee, I; Bloyer, S et al. (2010) Additional sex combs-like 1 belongs to the enhancer of trithorax and polycomb group and genetically interacts with Cbx2 in mice. Dev Biol 337:9-15
Muntean, Andrew G; Tan, Jiaying; Sitwala, Kajal et al. (2010) The PAF complex synergizes with MLL fusion proteins at HOX loci to promote leukemogenesis. Cancer Cell 17:609-21
Muntean, Andrew G; Giannola, Diane; Udager, Aaron M et al. (2008) The PHD fingers of MLL block MLL fusion protein-mediated transformation. Blood 112:4690-3
Caslini, Corrado; Yang, Zhaohai; El-Osta, Mohamad et al. (2007) Interaction of MLL amino terminal sequences with menin is required for transformation. Cancer Res 67:7275-83
Mueller, Dorothee; Bach, Christian; Zeisig, Deniz et al. (2007) A role for the MLL fusion partner ENL in transcriptional elongation and chromatin modification. Blood 110:4445-54
Hess, Jay L; Bittner, Claudia B; Zeisig, Deniz T et al. (2006) c-Myb is an essential downstream target for homeobox-mediated transformation of hematopoietic cells. Blood 108:297-304
Milne, Thomas A; Martin, Mary Ellen; Brock, Hugh W et al. (2005) Leukemogenic MLL fusion proteins bind across a broad region of the Hox a9 locus, promoting transcription and multiple histone modifications. Cancer Res 65:11367-74
Zeisig, Deniz T; Bittner, Claudia B; Zeisig, Bernd B et al. (2005) The eleven-nineteen-leukemia protein ENL connects nuclear MLL fusion partners with chromatin. Oncogene 24:5525-32
Hughes, Christina M; Rozenblatt-Rosen, Orit; Milne, Thomas A et al. (2004) Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell 13:587-97
Martin, Mary Ellen; Milne, Thomas A; Bloyer, Sebastien et al. (2003) Dimerization of MLL fusion proteins immortalizes hematopoietic cells. Cancer Cell 4:197-207

Showing the most recent 10 out of 13 publications