The t(8,21) is perhaps the most frequent chromosomal translocation associated with acute myeloid leukemia. This translocation fuses the DNA binding domain of AML1, to nearly all of ETO. ETO does not appear to bind DNA directly, but it interacts with co-repressors such as N-CoR, mSin3, and histone deacetylases-1, -2, and -3, and acts as a co-repressor by interacting with DNA binding proteins such as the PLZF transcriptional repressor Our preliminary studies indicate that AML1-ETO represses the endogenous promoter of the p14 ARF tumor suppressor. ARF is a component of the """"""""oncogene checkpoint"""""""" and regulates p53 protein stability in response to oncogene activation. The levels of ARF are lower in t(8,21)-containing -ML samples and expression of AML1-ETO blocked oncogenic induction of ARF expression in primary murine myeloid progenitor cells. Based on this preliminary data, we hypothesize that AML1-ETO inactivates the oncogene checkpoint to """"""""immortalize"""""""" HSC and myeloid progenitor cells, allowing the accumulation of further oncogenic mutations that cause AML. We have also identified the neurofibromatosis-1 (NF1) tumor suppressor as a second gene regulated by AML1-ETO. Leukemic blasts containing the t(8,21) have significantly lower levels of NF1 mRNA than other AML subgroups or the same subgroup (FAB M2) lacking the t(8,21). Therefore, we further hypothesize that repression of NF1 by AML1-ETO potentiates the oncogenic effects of secondary mutation of components of the RAS signaling pathway that are found in t(8,21)-containing AML. We propose to define the role of co-repressors that are recruited by AML1-ETO, and define the contribution of repression of the ARF and NF1 tumor suppressors to leukemogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064140-13
Application #
6850654
Study Section
Special Emphasis Panel (ZRG1-CPA (02))
Program Officer
Mufson, R Allan
Project Start
1994-07-01
Project End
2008-02-28
Budget Start
2005-03-01
Budget End
2006-02-28
Support Year
13
Fiscal Year
2005
Total Cost
$319,365
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Heaster, Tiffany M; Walsh, Alex J; Zhao, Yue et al. (2018) Autofluorescence imaging identifies tumor cell-cycle status on a single-cell level. J Biophotonics 11:
Stengel, Kristy R; Barnett, Kelly R; Wang, Jing et al. (2017) Deacetylase activity of histone deacetylase 3 is required for productive VDJ recombination and B-cell development. Proc Natl Acad Sci U S A 114:8608-8613
Liu, Qi; Wang, Jing; Zhao, Yue et al. (2017) Identification of active miRNA promoters from nuclear run-on RNA sequencing. Nucleic Acids Res 45:e121
Kim, H-G; LeGrand, J; Swindle, C S et al. (2017) The assembly competence domain is essential for inv(16)-associated acute myeloid leukemia. Leukemia 31:2267-2271
Zhao, Yue; Liu, Qi; Acharya, Pankaj et al. (2016) High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML. Cell Rep 16:2003-16
Adams, Clare M; Hiebert, Scott W; Eischen, Christine M (2016) Myc Induces miRNA-Mediated Apoptosis in Response to HDAC Inhibition in Hematologic Malignancies. Cancer Res 76:736-48
Stengel, Kristy R; Zhao, Yue; Klus, Nicholas J et al. (2015) Histone Deacetylase 3 Is Required for Efficient T Cell Development. Mol Cell Biol 35:3854-65
Williams, Christopher S; Bradley, Amber M; Chaturvedi, Rupesh et al. (2013) MTG16 contributes to colonic epithelial integrity in experimental colitis. Gut 62:1446-55
Wells, Christina E; Bhaskara, Srividya; Stengel, Kristy R et al. (2013) Inhibition of histone deacetylase 3 causes replication stress in cutaneous T cell lymphoma. PLoS One 8:e68915
Summers, Alyssa R; Fischer, Melissa A; Stengel, Kristy R et al. (2013) HDAC3 is essential for DNA replication in hematopoietic progenitor cells. J Clin Invest 123:3112-23

Showing the most recent 10 out of 69 publications