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 #
5R01CA129037-07
Application #
8642146
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Pelroy, Richard
Project Start
2007-08-08
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
7
Fiscal Year
2014
Total Cost
$284,560
Indirect Cost
$118,883
Name
Yale University
Department
Pathology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Gu, Peili; Jia, Shuting; Takasugi, Taylor et al. (2018) CTC1-STN1 coordinates G- and C-strand synthesis to regulate telomere length. Aging Cell :e12783
Chen, Cong; Gu, Peili; Wu, Jian et al. (2017) Structural insights into POT1-TPP1 interaction and POT1 C-terminal mutations in human cancer. Nat Commun 8:14929
Rai, Rekha; Hu, Chunyi; Broton, Cayla et al. (2017) NBS1 Phosphorylation Status Dictates Repair Choice of Dysfunctional Telomeres. Mol Cell 65:801-817.e4
Gu, P; Wang, Y; Bisht, K K et al. (2017) Pot1 OB-fold mutations unleash telomere instability to initiate tumorigenesis. Oncogene 36:1939-1951
Hu, Chunyi; Rai, Rekha; Huang, Chenhui et al. (2017) Structural and functional analyses of the mammalian TIN2-TPP1-TRF2 telomeric complex. Cell Res 27:1485-1502
Rai, Rekha; Chen, Yong; Lei, Ming et al. (2016) TRF2-RAP1 is required to protect telomeres from engaging in homologous recombination-mediated deletions and fusions. Nat Commun 7:10881
Wang, Yang; Wang, Xinwei; Flores, Elsa R et al. (2016) Dysfunctional telomeres induce p53-dependent and independent apoptosis to compromise cellular proliferation and inhibit tumor formation. Aging Cell 15:646-60
Lee, Youngsoo; Brown, Eric J; Chang, Sandy et al. (2014) Pot1a prevents telomere dysfunction and ATM-dependent neuronal loss. J Neurosci 34:7836-44
Gupta, Romi; Dong, Yuying; Solomon, Peter D et al. (2014) Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A. Proc Natl Acad Sci U S A 111:E3062-71
Chang, Sandy (2013) Cancer chromosomes going to POT1. Nat Genet 45:473-5

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