Fusion of the mixed lineage leukemia protein (MLL) to one of over 50 different translocation partners converts it into a potent leukemogenic oncoprotein. The resulting fusion proteins transform by upregulation of A cluster Hox genes including Hoxa9 and the Hox cofactor Meis1. We have made considerable progress toward understanding the mechanism of transcriptional regulation by MLL and MLL fusion proteins. We discovered that MLL is a histone H3 lysine 4 methyltransferase that regulates transcription by direct binding to both Hox and Meis1 promoters and coding regions. We found that MLL interacts with the tumor suppressor menin via a small amino terminal domain and that this interaction is important for both the function of normal MLL as well as for MLL fusion proteins. Our overriding goal is to facilitate the development of more effective therapies for leukemias with MLL rearrangements. To this end, the proposed experiments will analyze several mechanisms pivotal for transformation by MLL fusion proteins. Some MLL fusion proteins fuse MLL to transcriptional activators while others dimerize the truncated MLL molecule. Both classes share the MLL amino terminus, which is required for transformation. In SA#1 we will analyze the role of the interaction of the MLL amino terminus with menin in transformation by both classes of MLL fusion proteins. SA#2 focuses on the most common MLL fusion proteins, involving translocation partners AF4, ENL, AF9 and AF5q31, which account for more than 70% of MLL-associated leukemias. All four proteins are physically associated in a complex called MPAC (MLL Partner Activation Complex) that includes Dot1, a histone H3 lysine 79 methyltransferase, and CDK9/CyclinT1/T2, which phosphorylates the C terminal domain of RNA polymerase II. We will study the mechanism of transcriptional activation by MPAC in both normal hematopoiesis and when recruited to target loci by leukemogenic MLL fusion proteins. Surprisingly, MPAC also contains Pc3 and Ring1B, two members of the repressive Polycomb group protein family. We will determine if this enzymatic activity of these proteins is intact in the context of MPAC and whether MLL fusion proteins prevent Polycomb-mediated silencing. SA#3 assesses the role of MPAC kinase and histone methyltransferase activity on fusion protein-mediated transformation. Studies of these potential """"""""Achilles heels"""""""" will provide valuable insights into how normal transcriptional mechanisms are disrupted by MLL fusion proteins and how these may be targeted therapeutically.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA092251-09
Application #
7677856
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Mufson, R Allan
Project Start
2001-07-01
Project End
2012-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
9
Fiscal Year
2009
Total Cost
$269,485
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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