Mature B cell lymphomas are a diverse set of diseases which share the property of having failed to complete the differentiation process into plasma cells or undergo apoptosis. PRDI-BF1 and its murine homologue Blimp-1 are transcriptional repressors and act as a molecular switch to commit activated B cells to become non-dividing plasma cells or undergo apoptosis. In this role PRDI-BF1 has broad significance for normal humoral immune responses and in malignancies of mature B cells and plasma cells. We hypothesize that failure to induce PRDI-BF1 expression or function contributes to the persistence of lymphomas and as such therapies designed to rescue PRDI-BF1 function may be important in treating lymphoma. Artificial overexpression of PRDI-BF1 leads to apoptosis in multiple lymphoma lines. Furthermore the hypothesis is supported by our finding that treatment of lymphoma cells with chemotherapeutic agents such as proteasome or histone deacetylase inhibitors leads to an early induction of PRDI-BF1 expression. We have made the recent discovery that PRDI-BF1 directly recruits the histone methyltransferase G9a to mediate silencing of interferon-beta. This suggests chromatin remodeling is the means by which PRDI-BF1 drives terminal differentiation of B cells and kills lymphoma cells. The impact of chromatin remodeling driven by PRDI-BF1 in this process will be investigated. PRDI-BF1 is transcriptionally regulated by unknown mechanisms. This will be investigated and will provide the first detailed understanding of transcriptional regulation at this critical developmental time point and may suggest new avenues to induce PRDI-BF1. Finally, PRDI-BF1 function requires a highly conserved SET-like domain but its activity is unknown. We will identify the proteins interacting at this site and determine their role in PRDI-BF1 activity. Thus this proposal will shed new light on the events occurring during differentiation and may indicate new targets to affect the growth and persistence of lymphomas. ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114504-04
Application #
7406054
Study Section
Special Emphasis Panel (ZRG1-ONC-Q (01))
Program Officer
Howcroft, Thomas K
Project Start
2005-07-27
Project End
2010-05-31
Budget Start
2008-06-01
Budget End
2009-05-31
Support Year
4
Fiscal Year
2008
Total Cost
$230,795
Indirect Cost
Name
H. Lee Moffitt Cancer Center & Research Institute
Department
Type
DUNS #
139301956
City
Tampa
State
FL
Country
United States
Zip Code
33612
Pan, Hongjie; O'Brien, Thomas F; Wright, Gabriela et al. (2013) Critical role of the tumor suppressor tuberous sclerosis complex 1 in dendritic cell activation of CD4 T cells by promoting MHC class II expression via IRF4 and CIITA. J Immunol 191:699-707
Smith, Matthew A; Wright, Gabriela; Wu, Jian et al. (2011) Positive regulatory domain I (PRDM1) and IRF8/PU.1 counter-regulate MHC class II transactivator (CIITA) expression during dendritic cell maturation. J Biol Chem 286:7893-904
Cubedo, Elena; Maurin, Michelle; Jiang, Xiaoyu et al. (2011) PRDM1/Blimp1 downregulates expression of germinal center genes LMO2 and HGAL. FEBS J 278:3065-75
Lin, J; Lwin, T; Zhao, J-J et al. (2011) Follicular dendritic cell-induced microRNA-mediated upregulation of PRDM1 and downregulation of BCL-6 in non-Hodgkin's B-cell lymphomas. Leukemia 25:145-52
Vrzalikova, Katerina; Vockerodt, Martina; Leonard, Sarah et al. (2011) Down-regulation of BLIMP1? by the EBV oncogene, LMP-1, disrupts the plasma cell differentiation program and prevents viral replication in B cells: implications for the pathogenesis of EBV-associated B-cell lymphomas. Blood 117:5907-17
Smith, Matthew A; Maurin, Michelle; Cho, Hyun Il et al. (2010) PRDM1/Blimp-1 controls effector cytokine production in human NK cells. J Immunol 185:6058-67
Desai, Shruti; Maurin, Michelle; Smith, Matthew A et al. (2010) PRDM1 is required for mantle cell lymphoma response to bortezomib. Mol Cancer Res 8:907-18
Desai, Shruti; Bolick, Sophia C E; Maurin, Michelle et al. (2009) PU.1 regulates positive regulatory domain I-binding factor 1/Blimp-1 transcription in lymphoma cells. J Immunol 183:5778-87
Zhao, Mojun; Flynt, Frederick L; Hong, Mei et al. (2007) MHC class II transactivator (CIITA) expression is upregulated in multiple myeloma cells by IFN-gamma. Mol Immunol 44:2923-32
Chen, Han; Gilbert, Carolyn A; Hudson, John A et al. (2007) Positive regulatory domain I-binding factor 1 mediates repression of the MHC class II transactivator (CIITA) type IV promoter. Mol Immunol 44:1461-70