Rearrangements of the mixed lineage leukemia gene (MLL) are associated with aggressive lymphoid and myeloid leukemias in both children and adults. MLL, which is homologous to Drosophila Trithorax, is one of a growing family of epigenetic regulators of transcription including CBP, MOZ, and IN11 implicated in human malignancies. Fusion of MLL to one of more than 25 different translocation partners, which in general share little sequence homology, converts it into a leukemogenic oncoprotein. The mechanism of transformation by MLL fusion proteins is poorly understood although it undoubtedly involves transcriptional deregulation of target genes. Efforts to study this function has been hampered by the lack of knowledge of target genes that has both precluded studies of alterations in signal transduction pathways, as well as functional studies to discern mechanisms of activation at target promoters. We have now identified a c-MYC-dependent promoter that is strongly transactivated by 5 different MLL fusion proteins as well as by dimerized or exon-duplicated forms of MLL resembling those occurring in human leukemias. Our data indicate that domains of MLL and translocation partners required for transactivation are also required for transformation, and also that transactivation is dependent on the ATPase-dependent SWI/SNF chromatin remodeling complex. Our overall goal is to better define how MLL fusion proteins deregulate expression of target genes. To this end 1) The role of dimerization and oligomerization of MLL in transactivation and transformation will be defined, and the effect of mutagenesis of four conserved domains of MLL on these functions will be assessed. 2) Direct targets of MLL fusion proteins will be identified. 3) We will determine if MLL induced leukemia is reversible. 4) The role of the SWI/SNF complex in MLL fusion protein transactivation and transformation will be explored.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092251-06
Application #
7034595
Study Section
Special Emphasis Panel (ZRG1-CPA (03))
Program Officer
Mufson, R Allan
Project Start
2002-04-01
Project End
2007-03-31
Budget Start
2006-04-01
Budget End
2007-03-31
Support Year
6
Fiscal Year
2006
Total Cost
$259,556
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
Maethner, Emanuel; Garcia-Cuellar, Maria-Paz; Breitinger, Constanze et al. (2013) MLL-ENL inhibits polycomb repressive complex 1 to achieve efficient transformation of hematopoietic cells. Cell Rep 3:1553-66
Monroe, Sara C; Jo, Stephanie Y; Sanders, Daniel S et al. (2011) MLL-AF9 and MLL-ENL alter the dynamic association of transcriptional regulators with genes critical for leukemia. Exp Hematol 39:77-86.e1-5
Jo, Stephanie Y; Granowicz, Eric M; Maillard, Ivan et al. (2011) Requirement for Dot1l in murine postnatal hematopoiesis and leukemogenesis by MLL translocation. Blood 117:4759-68
Tan, Jiaying; Jones, Morgan; Koseki, Haruhiko et al. (2011) CBX8, a polycomb group protein, is essential for MLL-AF9-induced leukemogenesis. Cancer Cell 20:563-75
Tan, Jiaying; Muntean, Andrew G; Hess, Jay L (2010) PAFc, a key player in MLL-rearranged leukemogenesis. Oncotarget 1:461-5
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
Fisher, Cynthia L; Pineault, Nicolas; Brookes, Christy et al. (2010) Loss-of-function Additional sex combs like 1 mutations disrupt hematopoiesis but do not cause severe myelodysplasia or leukemia. Blood 115:38-46
Caslini, Corrado; Connelly, James A; Serna, Amparo et al. (2009) MLL associates with telomeres and regulates telomeric repeat-containing RNA transcription. Mol Cell Biol 29:4519-26
Muntean, Andrew G; Hess, Jay L (2009) Epigenetic dysregulation in cancer. Am J Pathol 175:1353-61

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