The goal of this project is to better understand the biology of acute myeloid leukemia (AML) in Down syndrome (DS) children related to the association of the chromosome 21-localized gene, cystathionine-beta- synthase (CBS) and response to cytosine arabinoside (ara-C)-based therapy. Childhood AML has the worst prognosis of all major childhood cancers with five year relative survival rates of approximately 37%. In contrast, DS children with AML represent an unique group of leukemia patients in view of having significantly higher event-free survival (EFS) rates (70-100% with relapse rates < 15%) compared to non-DS children when treated with ara-C-based protocols. Thus, identifying the biological basis for the extremely high cure rates of DS AML patients can have very important implications and potentially can lead to improvements in AML therapy for all patients. Our previous results have begun to shed light on the underlying mechanisms responsible for the striking increased EFS in DS AML patients. Our results demonstrating i) significantly increased CBS transcript levels in DS myeloblasts and a correlation with in vitro ara-C sensitivity and ara-CTP generation, ii) dramatic increased in ara-C metabolism to ara-CTP in vitro in leukemia cell lines transfected with the CBS cDNA, associated with increased in vitro and in vivo ara-C sensitivity, and iii) significant differences in frequency of the 844ins68 CBS gene polymorphism in DS myeloblasts, provide compelling evidence of an integral relationship between CBS gene expression and ara-C metabolism. This mechanisms is likely a major factor that accounts for the increased chemotherapy sensitivity and high cure rates of pediatric DS AML patients. This study will continue to examine over novel hypothesis and laboratory observations which bridge basic research (e.g., understanding the transcriptional regulation of CBS, determining the relation of CBS mutations/polymorphisms and ara-C metabolism) and apply this work to translational studies using clinical leukemia samples. These findings may ultimately be applied clinically to improve the treatment and cure of AML.
The specific aims of the study are: 1) To characterize the transcriptional regulation of the CBS gene in leukemia cell lines and clinical leukemia samples; 2) To develop CBS-transfected AML cell models and to determine the mechanistic basis for the effects of CBS on ara-C metabolism and sensitivity; 3) To determine the relationships between CBS gene expression and ara-C sensitivities in patient myeloblasts with wild-type CBS and with the T833C, G919A, 844ins68 CBS gene variants.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA092308-01
Application #
6364884
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Wu, Roy S
Project Start
2001-07-01
Project End
2006-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
1
Fiscal Year
2001
Total Cost
$234,675
Indirect Cost
Name
Wayne State University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Detroit
State
MI
Country
United States
Zip Code
48202
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