Abstract

The ALL-1 gene is directly involved in acute leukemia in particular in infants and in patients with therapy-related disease. The ALL-1 gene alterations consist predominantly of chromosome translocations or partial tandem duplications. ALL-1 is the human homologue of Drosophila trithorax which plays an important role during Drosophila development. The experiments proposed here are intended to provide an understanding of the mechanisms by which ALL-1 gene alterations induce leukemia, as well as of the mode of action of normal ALL-1 and TRITHORAX. Investigations will include: 1) developing of a mouse model to assay leukemogenicity of the partially duplicated ALL-1. 2) assessing potential role of ALL-1 chimeric 1 fusion proteins, 3) characterization of genes which are turned on or off by ALL-1 fusion proteins, 4) identification and detailed characterization of trithorax and ALL-1 DNA response elements, 5) identification and purification of a multi-protein complexes containing ALL-1 and TRX. 6) identification of proteins which physically interact with highly conserved motifs within the ALL-1 and TRITHORAX proteins. 8) Functional and biochemical characterization of the product of the recently cloned human gene homologous to Drosophila ash1.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
2P01CA050507-06A1
Application #
6038151
Study Section
Special Emphasis Panel (ZCA1-GRB-I (O1))
Program Officer
Mufson, R Allan
Project Start
1994-07-01
Project End
2005-02-28
Budget Start
2000-03-24
Budget End
2001-02-28
Support Year
6
Fiscal Year
2000
Total Cost
$1,106,271
Indirect Cost

  Institution

Name
Thomas Jefferson University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
061197161
City
Philadelphia
State
PA
Country
United States
Zip Code
19107

  Publications

Petruk, Svetlana; Black, Kathryn L; Kovermann, Sina K et al. (2013) Stepwise histone modifications are mediated by multiple enzymes that rapidly associate with nascent DNA during replication. Nat Commun 4:2841
Petruk, Svetlana; Sedkov, Yurii; Johnston, Danika M et al. (2012) TrxG and PcG proteins but not methylated histones remain associated with DNA through replication. Cell 150:922-33
Johnston, Danika M; Sedkov, Yurii; Petruk, Svetlana et al. (2011) Ecdysone- and NO-mediated gene regulation by competing EcR/Usp and E75A nuclear receptors during Drosophila development. Mol Cell 44:51-61
Petruk, Svetlana; Sedkov, Yurii; Brock, Hugh W et al. (2007) A model for initiation of mosaic HOX gene expression patterns by non-coding RNAs in early embryos. RNA Biol 4:1-6
Petruk, Svetlana; Sedkov, Yurii; Riley, Kristen M et al. (2006) Transcription of bxd noncoding RNAs promoted by trithorax represses Ubx in cis by transcriptional interference. Cell 127:1209-21
Krajewski, Wladyslaw A; Nakamura, Tatsuya; Mazo, Alexander et al. (2005) A motif within SET-domain proteins binds single-stranded nucleic acids and transcribed and supercoiled DNAs and can interfere with assembly of nucleosomes. Mol Cell Biol 25:1891-9
Canaani, E; Nakamura, T; Rozovskaia, T et al. (2004) ALL-1/MLL1, a homologue of Drosophila TRITHORAX, modifies chromatin and is directly involved in infant acute leukaemia. Br J Cancer 90:756-60
Smith, Sheryl T; Petruk, Svetlana; Sedkov, Yurii et al. (2004) Modulation of heat shock gene expression by the TAC1 chromatin-modifying complex. Nat Cell Biol 6:162-7
Petruk, Svetlana; Sedkov, Yurii; Smith, Sheryl T et al. (2004) Purification and biochemical properties of the Drosophila TAC1 complex. Methods Enzymol 377:255-66
Nakamura, Tatsuya; Mori, Toshiki; Tada, Shinichiro et al. (2002) ALL-1 is a histone methyltransferase that assembles a supercomplex of proteins involved in transcriptional regulation. Mol Cell 10:1119-28

Showing the most recent 10 out of 31 publications