Genetics and epigenetics of lymphocyte development and transformation
Our group has three long-term goals:

1) To dissect at the molecular level the key events that guide the transition of B cells through the sequential stages of the GC reaction. For this purpose, a series of conditional mouse mutant strains in which deletion of genes coding for a defined set of transcription factors, signaling proteins, surface receptors and chromatin remodeling enzymes will be specifically induced in GC B cells. The role of these factors in the control of GC B cell survival, selection and terminal differentiation will be determined. Also, their involvement in regulating Ig somatic mutation and class-switch recombination will be investigated. A similar approach will be followed to dissect the role of a defined set of microRNAs in GC B cell responses.
2) To identify key genetic determinants controlling GC B-cell lymphoma initiation, maintenance and progression. Using existing mouse models of different subtypes of non-Hodgkin B cell lymphomas, we will delete in a conditional manner in lymphoma cells, at different stages of tumorigenesis, genes thought to play a critical role in (GC) B cell survival, proliferation and differentiation. The latter approach will be complemented by studies in which primary lymphoma cells of the different tumor subtypes will be transplanted into syngeneic recipient after infection with a library of lentiviral vectors expressing in an inducible manner short interfering RNAs directed against genes (initially B-cell specific) controlling specific functions of GC B cells. A major effort will be given to study the role of the BCR and its downstream signaling mediators in tumor B cell survival/proliferation. The final goal of these studies is to identify new therapeutic targets for the treatment of the different forms of GC B-cell malignancies.
3) Tumor initiation, maintenance and progression results from functional cooperation between two or more oncogenes, often associated with loss of tumor suppressor gene activity. In this context, our group aims to identify partners of oncogenes whose function is commonly deregulated in specific forms of non-Hodgkin lymphomas including BL, FL and DLBCL. For this purpose, in mouse models of non-Hodgkin B cell lymphomas expressing the dominant oncogene as a transgene, insertional mutagenesis will be specifically induced in GC B cells. Acceleration of lymphoma onset in lymphoma-prone mice will confirm functional cooperation between oncogenes, eventually associated with loss of tumor suppressor gene function. The genes cooperating with the "primary" oncogene to accelerate disease will be cloned with PCR-based methods from genomic DNA extracted from a series of independent primary lymphomas. The biological relevance of the newly identified gene products will be validated analyzing their expression andactivation status in a series of primary human lymphoma specimens representative of the different types of non-Hodgkin B cell lymphomas. A similar approach will be attempted to identify oncogenic partners of the Epstein Barr Virus (EBV)-encoded proteins LMP1 and LMP2A expressed in the Hodgkin-Reed Sternberg tumor cells of EBV+ cases of classical Hodgkin lymphoma. For this purpose we will use mice, available in the lab, which express the viral proteins in a conditional manner.

1)Grazini U, Zanardi F, Citterio E, Casola S, Goding CR, McBlane F.
The RING domain of RAG1 ubiquitylates histone H3: a novel activity in chromatin-mediated regulation of V(D)J joining.
Mol Cell. 2010 Jan 29;37(2):282-93.
2)Omoei D, Acampora D, Russo F, De Filippi R, Severino V, Di Francia R, frigeri F, Mancuso P, De Chiara A, Pinto* A, Casola S*, Simeone A*.
Expression of the brain transcription factor OTX1 occurs in a subset of normal germinal-center B cells and in aggressive Non-Hodgkin Lymphoma
Am J Pathol. 2009 Dec;175(6):2609-17.
* corresponding author
3)De Santa F, Narang V, Yap ZH, Tusi BK, Burgold T, Austenaa L, Bucci G, Caganova M, Notarbartolo S, Casola S, Testa G, Sung WK, Wei CL, Natoli G.
Jmjd3 contributes to the control of gene expression in LPS-activated macrophages.
EMBO J. 2009 Nov 4;28(21):3341-52.
4) Hikida M, Casola S, Takahashi N, Kaji T, Takemori T, Rajewsky K, Kurosaki T.
LC-{gamma}2 is essential for formation and maintenance of memory B cells.
J Exp Med. 2009 Mar 9. [Epub ahead of print]
5)Hao Z, Duncan GS, Seagal J, Su YW, Hong C, Haight J, Chen NJ, Elia A, Wakeham A, Li WY, Liepa J, Wood GA, Casola S, Rajewsky K, Mak TW.
Fas Receptor Expression in Germinal-Center B Cells Is Essential for T and B Lymphocyte Homeostasis.
Immunity. 2008 Oct;29(4):615-27.
Hömig-Hölzel C, Hojer C, Rastelli J, Casola S, Strobl LJ, Müller W, Quintanilla-6)Martinez L, Gewies A, Ruland J, Rajewsky K, Zimber-Strobl U.
Constitutive CD40 signaling in B cells selectively activates the noncanonical NF-kappaB pathway and promotes lymphomagenesis. J Exp Med. 2008 Jun 9;205(6):1317-29.
J Exp Med. 2008 Jun 9;205(6):1317-29. Epub 2008 May 19.
7)Thai TH, Calado DP, Casola S, Ansel KM, Xiao C, Xue Y, Murphy A, Frendewey D, Valenzuela D, Kutok JL, Schmidt-Supprian M, Rajewsky N, Yancopoulos G, Rao A, Rajewsky K.
Regulation of the germinal center response by microRNA-155.
Science. 2007; 316(5824):604-8.
8)Casola S
Control of peripheral B-cell development
Curr Opin Immunol. 2007 Apr;19(2):143-9.
Casola S* and Rajewsky K.
B cell recruitment and selection in mouse GALT germinal centres.
Curr Top Microbiol Immunol. 2006.; 308:155-171
* corresponding author
9)Klein U, Casola S., Cattoretti G, Shen Q, Lia M, Mo T, Ludwig T, Rajewsky K and Dalla-Favera R. 2006.
Transcription factor IRF4 controls plasma cell differentiation and class-switch recombination.
Nat Immunol. 2006; 7(7):773-82.
10)Casola S*, Cattoretti G, Uyttersprot N, Koralov SB, Segal J, Hao Z, Waisman A, Egert A, Ghitza D and Rajewsky K.
Tracking germinal center B cells expressing germ-line immunoglobulin {gamma}1 transcripts by conditional gene targeting.
Proc Natl Acad Sci U S A. 2006; 103(19): 7396-401.
* corresponding author
11)Novobrantseva TI, Majeau GR, Amatucci A, Kogan S, Brenner I, Casola S, Shlomchik MJ, Koteliansky V, Hochman PS and Ibraghimov A.
Attenuated liver fibrosis in the absence of B cells.
J Clin Invest. 2005; 115 (11):3072-82.

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