About 10 to 30% of ataxia-telangiectasia (A-T) patients develop leukemias or lymphomas. There is considerable interpatient variation in the age of onset and leukemia/lymphoma type. The incomplete penetrance and variable age of onset may be attributable to several factors. These include competing mortality from neurodegeneration and interstitial lung disease, and allele specific effects of ATM gene mutations. Also, there is limited evidence from clinical observations and studies using Atm knockout mice that modifier genes may account for some variation in leukemia/lymphoma susceptibility. We have introgressed the Atmtm1Awb knockout allele (Atm-) onto several inbred murine strains and observed differences in survival between Atm-/- mice on the different strain backgrounds. The primary aim of this proposal is to characterize the incidence and onset latency of thymic lymphoma in these Atm-/- congenic strains as a prelude to identifying lymphomagenesis modifier genes. A secondary aim is to assay aged Atm-/- mice for neurodegeneration and interstitial lung disease, since these clinically important phenotypes are not recapitulated in existing Atm knockout mouse strains. PUBLIC HEALTH RELEVELANCE: The major causes of death in ataxia-telangiectasia (A-T) patients are interstitial lung disease and cancer, specifically leukemias and lymphomas. This project aims to characterize a potential animal model for A-T that can be used to determine why some patients get leukemia and others don't. The model may also be useful for the testing of potential therapies against interstitial lung disease and neurodegeneration in A-T patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Small Research Grants (R03)
Project #
5R03CA135528-02
Application #
7624285
Study Section
Special Emphasis Panel (ZRG1-ONC-U (92))
Program Officer
Mietz, Judy
Project Start
2008-06-01
Project End
2010-05-31
Budget Start
2009-06-01
Budget End
2010-05-31
Support Year
2
Fiscal Year
2009
Total Cost
$73,500
Indirect Cost
Name
Colorado State University-Fort Collins
Department
Public Health & Prev Medicine
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
Genik, Paula C; Bielefeldt-Ohmann, Helle; Liu, Xianan et al. (2014) Strain background determines lymphoma incidence in Atm knockout mice. Neoplasia 16:129-36