The most frequent cause of acute myeloid leukemia (AML) is the 8;21 translocation [t(8;21)], which results in transcriptional dysregulation. This translocation generates an AML1-ETO fusion protein by joining part of the AML1/RUNX1 transcription factor to a nearly complete ETO protein, the prototypical member of a family of transcriptional corepressors. The long-term goal of this proposal is to learn how to selectively interfere with AML1-ETO activity, and thereby reverse the leukemogenic state. The immediate goal of this application is to understand the mechanisms by which AML1-ETO disrupts the normal transcriptional program. Aberrant expression of AML1-ETO is the pathological cause of t(8;21) AML. Phenotypic differences between the AML1 knockout and the AML1-ETO knock-in mouse models indicate that AML1-ETO has other activities besides deregulation of AML1 functions. Although it is now clear that AML1-ETO interferes with multiple cellular events involved in hematopoietic cell self-renewal, differentiation, and apoptosis, it remains unclear how AML1-ETO deregulates these pathways. Recently, Dr. Zhang discovered a molecular interaction between AML1-ETO and the class I helix-loop-helix transcriptional factors known as E proteins. Through the ETO domain, AML1-ETO aberrantly represses E protein-mediated transcription. E proteins have tumor- suppressor activities that are frequently inactivated in cancers. That is, they promote apoptosis and control hematopoietic cell differentiation. The leukemogenic potential of AML1-ETO is consistent with its inhibition of E protein functions related to both tumor suppression and regulation of cell differentiation. Dr. Zhang's preliminary studies show (i) that the ETO domains involved in repressing E protein- dependent transcription correlate with those involved in the leukemogenic activities of AML1-ETO; and (ii) that repression of E protein-dependent transcription by AML1-ETO involves not only chromatin-dependent inhibition, but also direct inhibition of the RNA polymerase II transcription complex. These findings led to the central hypothesis that AML1-ETO must repress both the chromatin-dependent and chromatin- independent transcription mediated by E proteins to allow for leukemogenesis. The hypothesis will be tested through the following two aims:
(Aim 1) To define the mechanisms by which AML1-ETO represses E protein-dependent transcription at the level of chromatin as well as at the level of basal transcription machinery;
and (Aim 2) To determine the extent to which inactivation of E proteins contributes to AML1-ETO leukemogenic function, and to elucidate the molecular pathways associated with E proteins in t(8;21) leukemic cells. A better understanding of the molecular mechanisms underlying t(8;21) AML, and the aberrant functions of proteins involved in leukemogenesis should lead to the identification of new therapeutic targets and strategies for treatment of AML.
Leukemia is a cancer of the blood that involves abnormal growth and differentiation of certain types of whiteblood cells. In some cases; leukemia is caused by a chromosomal abnormality that leads to inactivation of Eprotein; a cellular protein that normally controls blood cell differentiation and proliferation. This project willdefine the mechanism of E protein inactivation; which could lead to new treatments for leukemia based on thereactivation of this protein to reverse the leukemic condition.
|Welch, Ryan D; Guo, Chun; Sengupta, Monideepa et al. (2017) Rev-Erb co-regulates muscle regeneration via tethered interaction with the NF-Y cistrome. Mol Metab 6:703-714|
|Zhang, Jinsong; Gow, Chien-Hung; Khan, Sohaib et al. (2017) Transcriptional and Genomic Control of Stem Cells in Development and Cancer. Stem Cells Int 2017:2513598|
|Steinauer, Nickolas; Guo, Chun; Zhang, Jinsong (2017) Emerging Roles of MTG16 in Cell-Fate Control of Hematopoietic Stem Cells and Cancer. Stem Cells Int 2017:6301385|
|Li, Jian; Guo, Chun; Steinauer, Nickolas et al. (2016) New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins. Front Biol (Beijing) 11:285-304|
|Wong, Madeline M; Guo, Chun; Zhang, Jinsong (2014) Nuclear receptor corepressor complexes in cancer: mechanism, function and regulation. Am J Clin Exp Urol 2:169-87|
|Gow, Chien-Hung; Guo, Chun; Wang, David et al. (2014) Differential involvement of E2A-corepressor interactions in distinct leukemogenic pathways. Nucleic Acids Res 42:137-52|
|Feng, Yuxin; Singleton, David; Guo, Chun et al. (2013) DNA homologous recombination factor SFR1 physically and functionally interacts with estrogen receptor alpha. PLoS One 8:e68075|
|Benavides, Mario; Chow-Tsang, Lai-Fong; Zhang, Jinsong et al. (2013) The novel interaction between microspherule protein Msp58 and ubiquitin E3 ligase EDD regulates cell cycle progression. Biochim Biophys Acta 1833:21-32|
|Guo, Chun; Gow, Chien-Hung; Li, Yali et al. (2012) Regulated clearance of histone deacetylase 3 protects independent formation of nuclear receptor corepressor complexes. J Biol Chem 287:12111-20|
|Hu, Qiande; Guo, Chun; Li, Yali et al. (2011) LMO7 mediates cell-specific activation of the Rho-myocardin-related transcription factor-serum response factor pathway and plays an important role in breast cancer cell migration. Mol Cell Biol 31:3223-40|
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