A hallmark of many types of B cell lymphoma is chromosomal translocation, one type of genomic rearrangement, involving one of the immunoglobulin (Ig) loci and a proto-oncogene. Recurrent c-myc translocation is a classical example, often with Igh or Igl as translocation partners. c-myc rearrangements are observed in several aggressive B cell lymphomas including Burkitt lymphoma (BL, >90%), diffuse large B-cell lymphoma (DLBCL, 7-14%), plasmablastic lymphoma (~50%) and others. The presence of c-myc rearrangements in these diseases has critical diagnostic and prognostic implications. For example, c-myc rearrangements are associated with a poor prognosis in DLBCL patients treated with chemotherapy (e.g. R- CHOP). Thus, it is highly significant to elucidate the mechanisms of genomic rearrangements of c-myc. Such mechanistic studies will not only contribute significantly to our basic understanding of DNA repair but also guide the translational applications such as diagnosing aggressive B cell lymphomas or developing better therapeutic strategies. In this application, we propose to elucidate how differential DNA repair mechanisms operate in distinct B cell subpopulations to influence the level of c-myc genomic instability. Previous studies of Igh-c-myc translocation have resulted in a much deeper understanding of translocation mechanism, e.g. the role of activation-induced deaminase (AID) in generating DNA double stranded breaks (DSBs) at both Ig and c-myc loci. However, these previous studies have not considered the influence of activation status or microenvironment of B cells on the outcome of DNA repair pathways. AID is a central player of antibody diversity via inducing point mutations or DSBs at Ig loci. How AID-initiated lesions are prevented from inducing genome-wide damage is not completely understood. Prior studies proposed a differential DNA repair mechanism that protects certain non-Ig loci such as c-myc from AID attack. However, determinants that regulate such protective mechanisms remain largely unknown. Our preliminary studies reveal a complex interplay between target sequence, DNA repair mechanism, and activation or differentiation status of B cells, which appears to coordinately regulate genome stability at c-myc locus. We propose to employ our novel and unique mouse model and new techniques to elucidate the mechanisms regulating the occurrence of DSBs at c-myc locus in different subpopulations of B cells.

Public Health Relevance

Our studies will reveal the specific processes during which c-myc translocations arise and the mechanisms regulating the propensity of c-myc locus to form translocations. We will identify novel players that may either protect or disrupt the repair of c-myc DSBs. Finally, these studies will provide mechanistic insight into differential routes to AID-mediated genetic alterations in aggressive B cell lymphomas. Thus, our studies will greatly benefit the prevention, diagnosis, and treatment of B cell lymphomas.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA184707-01A1
Application #
8812432
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (O1))
Program Officer
Howcroft, Thomas K
Project Start
2014-12-01
Project End
2016-11-30
Budget Start
2014-12-01
Budget End
2015-11-30
Support Year
1
Fiscal Year
2015
Total Cost
$168,789
Indirect Cost
$60,039
Name
University of Colorado Denver
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Woolaver, Rachel A; Wang, Xiaoguang; Dollin, Yonatan et al. (2018) TRAF2 Deficiency in B Cells Impairs CD40-Induced Isotype Switching That Can Be Rescued by Restoring NF-?B1 Activation. J Immunol 201:3421-3430
Chen, Zhangguo; Gowan, Katherine; Leach, Sonia M et al. (2016) Unexpected effects of different genetic backgrounds on identification of genomic rearrangements via whole-genome next generation sequencing. BMC Genomics 17:823
Chen, Zhangguo; Elos, Mihret T; Viboolsittiseri, Sawanee S et al. (2016) Combined deletion of Xrcc4 and Trp53 in mouse germinal center B cells leads to novel B cell lymphomas with clonal heterogeneity. J Hematol Oncol 9:2
Chen, Zhangguo; Eder, Maxwell D; Elos, Mihret T et al. (2016) Interplay between Target Sequences and Repair Pathways Determines Distinct Outcomes of AID-Initiated Lesions. J Immunol 196:2335-47
Yeap, Leng-Siew; Hwang, Joyce K; Du, Zhou et al. (2015) Sequence-Intrinsic Mechanisms that Target AID Mutational Outcomes on Antibody Genes. Cell 163:1124-1137
Chen, Zhangguo; Getahun, Andrew; Chen, Xiaomi et al. (2015) Imbalanced PTEN and PI3K Signaling Impairs Class Switch Recombination. J Immunol 195:5461-5471