Recent molecular analyses have revealed at diagnosis, a striking heterogeneity with regard to the presence of acquired, prognostic chromosome aberrations, gene mutations and changes in gene expression in patients with acute myeloid leukemia (AML). Application of gene and microRNA-expression profiling has also identified expression signatures that appear to stratify AML patients within specific cytogenetic subsets into prognostic subgroups. These and similar future findings are likely to have a major impact on the clinical management of AML, not only for the prognostication process but also for the selection of appropriate treatments, since many of the identified genetic alterations constitute or will potentially become targets for specific therapeutic intervention. Using as a platform the Cancer and Leukemia Group B (CALGB) upfront treatment studies, we propose here to conduct definitive analyses that assess the frequencies and prognostic values of molecular abnormalities in a large population of AML patients. Further, we will integrate the information derived from the analysis of prognostic cytogenetic aberrations and gene mutations with that derived from the corresponding genome wide gene and microRNA expression profiles in order to gain biologic insights into leukemogenic mechanisms and identify "integrated functional signatures" that stratify patients into subsets "targetable" with specific therapeutic programs. We will achieve these goals through three Specific Aims: 1. To determine the frequency of molecular aberrations {e.g., FLT3 ITD, MLL PTD, NPM1, WT-1, CEBPA, RAS, KIT mutations and aberrant BAALC. ERG, FLT3, MNI and EVI1 over- expression) at diagnosis and to correlate them with clinical and laboratory characteristics and outcome in distinct cytogenetic subgroups of younger and older AML patients enrolled on CALGB treatment protocols; 2. To identify specific genome wide gene expression signatures at diagnosis and to correlate them with clinical and laboratory characteristics and outcome in distinct cytogenetic and molecular subgroups of younger and older AML patients enrolled on CALGB treatment protocols;3. To identify specific genome wide microRNA expression signatures at diagnosis and to correlate them with clinical and laboratory characteristics and outcome in distinct cytogenetic and molecular subgroups of younger and older AML patients enrolled on CALGB treatment protocols. We anticipate that completion of this research plan will allow risk-adapted stratification of AML patients into "personalized" treatment protocols designed to target the aberrant "functional" hematopoietic gene signatures that characterize distinct subsets of AML.

Public Health Relevance

Acute myeloid leukemia (AML) is one ofthe most common types of leukemia and is characterized by maturation arrest and proliferation of malignant cells in bone marrow and blood. Despite recent progress, most of patients die of their disease. Therefore, novel approaches that improve the outcome of these patients are highly needed. Here, we propose to characterize malignant cells from AML patients for genetic defects that can predict outcome. This approach will ultimately allow identification of subgroups of AML that will respond to specific and "personalized" treatments thereby improving the currently poor clinical outcome of these patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA140158-05
Application #
8521126
Study Section
Special Emphasis Panel (ZCA1-GRB-I)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
5
Fiscal Year
2013
Total Cost
$302,408
Indirect Cost
$59,737
Name
Ohio State University
Department
Type
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
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