Activation-Induced cytidine deaminase (AID) is expressed in germinal center B cells and is required for somatic hypermutation (SHM) and class switch recombination (CSR) of immunoglobulin genes. Aberrant targeting of AID to proto-oncogenes has also been implicated in the pathogenesis of B cell malignancies. AID has the potential to trigger mutations and chromosome instability throughout the genome but many genes are protected by high-fidelity DNA repair of AID-mediated events. The mechanisms responsible for guiding AID to its genetic target and determining whether a mutation will be repaired in a high-fidelity or low- fidelity manner are not understood. The central hypothesis underlying this proposal is that B cells have a specific mechanism for maintaining genomic stability in the face of SHM and CSR and that events leading to the breakdown of this mechanism contribute to AID-mediated genomic instability and malignant transformation. Here, a combination of animal and cell line models will be used to study the dynamic relationship of AID activity and DNA repair under both normal and neoplastic conditions.
In Specific Aim 1, mouse models of AID expression and DNA repair will be used to identify the lineage-specific mechanism that protects the B cell genome during SHM and investigate the contribution of AID-associated DNA repair pathways to the pathogenesis of lymphoid malignancy.
In Specific Aim 2, exogenous cellular stressors that perturb the balance of high-fidelity and low-fidelity DNA repair following AID activity will be characterized and used as a means for identifying factors that regulate the mutation threshold and in an actively mutating B cell.
In Specific Aim 3, the role of AID in the pathogenesis of B cell chronic lymphocytic leukemia (B-CLL) will be defined in a mouse model of this disease and the functional nature of AID will be characterized in human B-CLL cell lines and primary B-CLL specimens. We anticipate that this research will provide insight into the basic mechanism that regulates immune diversification in B cells and serve a long-term objective of identifying the molecular steps involved in the pathogenesis of lymphoid malignancy.

Public Health Relevance

(See Instructions): Aberrant targeting of natural immune diversification processes contributes to mutations of genes associated with certain types of leukemia and lymphoma of B cell origin. This research will serve to identify how genes are normally protected from this activity and will define how a breakdown of protective mechanisms leads to the development of hematologic cancers.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08CA140718-05
Application #
8510593
Study Section
Subcommittee G - Education (NCI)
Program Officer
Jakowlew, Sonia B
Project Start
2009-09-10
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
5
Fiscal Year
2013
Total Cost
$174,420
Indirect Cost
$12,920
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Gu, Xiwen; Shivarov, Velizar; Strout, Matthew P (2012) The role of activation-induced cytidine deaminase in lymphomagenesis. Curr Opin Hematol 19:292-8