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
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
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
Engel, Michael E; Nguyen, Hong N; Mariotti, Jolene et al. (2010) Myeloid translocation gene 16 (MTG16) interacts with Notch transcription complex components to integrate Notch signaling in hematopoietic cell fate specification. Mol Cell Biol 30:1852-63

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