Chronic lymphocytic leukemia is the most common adult leukemia in Western countries, with an estimated incidence of 3.9 per 100,000 people in the US and a median age of 72 years at time of diagnosis. A characteristic feature of this disease is its strikingly complex genomic profiles, highlighted by chromosome structural aberrations involving loss of chromosomes 11q, 13q, 17p and trisomy 13 [4,5]. These complex genetic alterations are thought to arise due to the stepwise accumulation of mutational changes in favor of tumor progression, initially in a genetically heterogeneous cell population, then by selection of more aggressive traits, such as the ability to metastasize into surrounding tissues. One important mechanism that protects against the acquisition of an unstable genome is proper function of telomeres, protein-DNA complexes that cap the ends of chromosomes. Dysfunctional telomeres undergo end-to-end chromosome fusions, resulting in an unstable genome observed in many diverse human cancers, including CLL. We hypothesize that telomere dysfunction in hematopoietic stem cells (HSCs) results in telomere dysfunction, driving genomic instability that results in the stepwise accumulation of mutational changes in favor of cancer progression, including the selection of p53 mutations during clonal evolution and progression to CLL. To test this hypothesis, we have generated a novel conditional knockout mouse model to delete mPOT1a/b in hematopoietic stem cells. As pioneers in the study of the role of POT1 in telomere end protection, we will utilize this highly innovative genetic tool, as wel as human CLL samples, to investigate the role of hPOT1 in CLL pathogenesis.

Public Health Relevance

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries, with an estimated incidence of 3.9 per 100,000 people in the US. We hypothesize that telomere dysfunction in hematopoietic stem cells (HSCs) results in telomere dysfunction, driving genomic instability that results in progression to CLL. We will test this hypothesis using knockout mouse models of telomere dysfunction to investigate the role of POT1 in CLL pathogenesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA129037-06A1
Application #
8504468
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Pelroy, Richard
Project Start
2007-08-08
Project End
2018-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
6
Fiscal Year
2013
Total Cost
$306,706
Indirect Cost
$122,406
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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