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.

Public Health Relevance

Leukemia is a cancer of the blood that involves abnormal growth and differentiation of certain types of white blood cells. In some cases, leukemia is caused by a chromosomal abnormality that leads to inactivation of E protein, a cellular protein that normally controls blood cell differentiation and proliferation. This project will define the mechanism of E protein inactivation, which could lead to new treatments for leukemia based on the reactivation of this protein to reverse the leukemic condition.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL093195-04
Application #
8293213
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Thomas, John
Project Start
2009-07-30
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$388,575
Indirect Cost
$141,075
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221