Projects and Grants per year
Grants and Contracts Details
Description
The long term goal of this project is to understand the molecular mechanisms underlying leukemia relapse.
There are more than 21,000 deaths to relapsed leukemia each year in the United States, but the molecular
basis of this deadly disease is still unknown. Since leukemia relapse is always associated with
chemotherapy, and since cells exposed to therapeutic agents usually acquire a mismatch repair (MMR)
deficient phenotype, we hypothesize that leukemia relapse in many cases is caused by a small fraction of
leukemic cells that have adopted an MMR deficient phenotype during the course of chemotherapy. Our
preliminary studies have showed that defects in MMR are indeed associated with cell lines derived from
relapsed leukemia and patients with relapsed leukemia. To further test our hypothesis, this application
proposes both genetic and biochemical approaches to analyze the relationship between relapsed leukemia
and MMR proficiency. First, real-time PCR will be used to analyze the status of microsatellite sequences in
adult acute leukemia patient samples at presentation, remission, and relapse to dynamically and
quantitatively determine how leukemic cells transform from a microsatellite stable form to a microsatellite
instable form during the development of relapse. Second, leukemic cells from relapsed patients will be
analyzed for genetic alterations and epigenetic modifications in key MMR genes such as hMSH2 and hMLH1
using combination technologies of PCR-based single strand conformation polymorphism, DNA sequencing,
and methylation-specific PCR. Third, individual alterations identified in leukemia patients will be introduced
into MMR genes to express recombinant mutant proteins. To determine the actual impact of these alterations
on MMR function, individual recombinant mutant proteins will be examined for their ability to restore MMR to
the corresponding MMR mutant extracts using an in vitro functional MMR assay. This study will provide
significant insight into the mechanism underlying leukemia relapse as well as vital information for designing
therapeutic regimens for the disease.
Status | Finished |
---|---|
Effective start/end date | 4/1/05 → 2/28/12 |
Funding
- National Cancer Institute: $1,318,882.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.
Projects
- 1 Finished
-
Diversity Supplement: DNA Mismatch Repair Deficiency and Leukemia Relapse
Gu, L. (PI)
8/1/07 → 2/28/12
Project: Research project