Chromosomal translocations target master regulatory genes that affect growth, differentiation, and apoptosis. The t(8;21) is perhaps the most frequent chromosomal translocation associated with acute myeloid leukemia. This translocation fuses the first 177aa of RUNX1 (formerly known as AML1), including the DNA binding domain, to nearly all of Myeloid Translocation Gene on chromosome 8 (MTG8, also known as ETO). In addition to its involvement in acute leukemia, MTG8 was recently identified as a candidate cancer gene in colorectal carcinoma (CRC). The targeting of MTG8 in two tumor types emphasizes the critical role this gene plays in tumorigenesis. Studies of the t(8;21) fusion protein indicate that MTG8 functions as a transcriptional co-repressor. This application is focused on defining the role that this master regulator of transcription plays in tumorigenesis. We will determine how the mutations of MTG8 that are associated with colorectal cancer affect its function both in vitro and in vivo. Biochemical approaches will define how these mutations affect MTG8 recruitment of co- repressors and histone deacetylases and how these changes alter transcriptional repression. We will also take advantage of Mtg8-deficient mice to define the physiological contributions of this gene to gut development. We will also test whether inactivation of this gene stimulates tumorigenesis and determine how the CRC-related mutations affect its functions in the intestinal epithelium. Finally, we will investigate the molecular mechanisms underlying the ability of the t(8;21) fusion protein to disrupt transcriptional programs regulated by endogenous MTG family members and the nuclear hormone co-repressors. This information will not only shed light on the molecular mechanism by which MTG8 contributes to AML, but will also provide insights to its role in colorectal carcinoma.

Public Health Relevance

The targeting of MTG8 in by the most frequent chromosomal translocation associated with acute myeloid leukemia and its mutation in colorectal carcinoma emphasizes the critical role that this gene plays in tumorigenesis. This application is focused on defining the role that this master regulator of transcription plays in tumorigenesis and how the mutations of MTG8, which are associated with colorectal cancer, affect its function both in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA064140-20
Application #
8387760
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Mufson, R Allan
Project Start
1994-07-01
Project End
2014-11-30
Budget Start
2012-12-01
Budget End
2014-11-30
Support Year
20
Fiscal Year
2013
Total Cost
$289,099
Indirect Cost
$100,761
Name
Vanderbilt University Medical Center
Department
Biochemistry
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
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
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
Fischer, Melissa A; Moreno-Miralles, Isabel; Hunt, Aubrey et al. (2012) Myeloid translocation gene 16 is required for maintenance of haematopoietic stem cell quiescence. EMBO J 31:1494-505
Hunt, Aubrey; Fischer, Melissa; Engel, Michael E et al. (2011) Mtg16/Eto2 contributes to murine T-cell development. Mol Cell Biol 31:2544-51
Barrett, Caitlyn W; Fingleton, Barbara; Williams, Amanda et al. (2011) MTGR1 is required for tumorigenesis in the murine AOM/DSS colitis-associated carcinoma model. Cancer Res 71:1302-12
Bhaskara, Srividya; Knutson, Sarah K; Jiang, Guochun et al. (2010) Hdac3 is essential for the maintenance of chromatin structure and genome stability. Cancer Cell 18:436-47
Yan, Ming; Ahn, Eun-Young; Hiebert, Scott W et al. (2009) RUNX1/AML1 DNA-binding domain and ETO/MTG8 NHR2-dimerization domain are critical to AML1-ETO9a leukemogenesis. Blood 113:883-6
Bhaskara, Srividya; Chyla, Brenda J; Amann, Joseph M et al. (2008) Deletion of histone deacetylase 3 reveals critical roles in S phase progression and DNA damage control. Mol Cell 30:61-72
Moore, Amy C; Amann, Joseph M; Williams, Christopher S et al. (2008) Myeloid translocation gene family members associate with T-cell factors (TCFs) and influence TCF-dependent transcription. Mol Cell Biol 28:977-87
Hanson, Caroline A; Wood, Lauren D; Hiebert, Scott W (2008) Cellular stress triggers TEL nuclear export via two genetically separable pathways. J Cell Biochem 104:488-98

Showing the most recent 10 out of 56 publications