Rearrangement of the mixed lineage leukemia gene (MLL, HRX, ALL-1) are associated with aggressive acute lymphoblastic leukemia in infants as well as acute myelogenous leukemia which often arises secondary to therapy with topoisomerase II inhibitors. MLL is the human homolog of Drosophila trithorax, a chromatic-associated protein that maintains homeobox (Hox) gene expression by blocking transcriptional repression by Polycomb group (Pc-G) proteins. Over twenty different MLL translocation partners have been identified which in general share little sequence homology. Possible mechanisms for MLL-mediated leukemogenesis include loss of function from truncation of the MLL protein, a gain of function mechanism produced by the chimeric protein, or a combination of loss of function and gain of function mechanisms. Given the ability of MLL to regulate Hox gene expression and the apparent importance of Hox genes in hematopoiesis, it is likely that deregulation of Hox expression by MLL fusion proteins plays a central role in leukemogenesis. Studying how MLL and MLL fusion proteins regulate these downstream target genes may provide important insights into the mechanism of MLL-mediate leukemogenesis. To this end the proposed research will 1) define domains of MLL that are required for Hox gene regulation, 2) identify the cis-acting DNA sequences that are required for MLL action and map these relative to sequences required for mammalian Pc-G repression, 3) identify Hox genes regulated by MLL in specific lineages, and 4) examine the effect of MLL fusion proteins on hematopoiesis and Hox gene expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
7R01CA078815-03
Application #
6140461
Study Section
Pathology B Study Section (PTHB)
Program Officer
Shen, Grace L
Project Start
1998-07-01
Project End
2003-04-30
Budget Start
1999-07-01
Budget End
2000-04-30
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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

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