Molecular mechanisms of oncogenesis

ITT Core Research Laboratory (CRL)

Villa delle Rose
Via Cosimo il Vecchio 2, 50139 Firenze
Tel: 055-32697858
Fax: 055-32697879

Molecular mechanisms of oncogenesis - team members Principal investigator: Silvo Conticello, MD

Team members
Cesare Sala PhD student
Francesco Severi PhD student
Giorgio Mattiuz  
Giulia Saraconi  


The Molecular Mechanisms of Oncogenesis Unit started its research activities in January 2008. Our research is focused on the identification and characterization of factors and pathways involved in the onset of genetic alterations in cancer.

Main research themes

Role of activation-induced deaminase in oncogenesis

Cancer is the outcome of a multistep path that progressively leads to uncontrolled cellular growth. Underlying this progression of events is the presence of genetic alterations or mutations that provide the framework, characterizing the type and evolution of the tumor. Mostly, we have access only to the ending point of this path - with the diagnosis of cancer - and it is not easy to intervene in this succession of events. However, understanding the factors and processes leading to the genetic alterations can improve our diagnostic and therapeutic options by a finer characterization of the tumorigenesis - the final aim being a more targeted treatment.

Surprisingly there is a class of enzymes, the AID/APOBECs, whose only role is to introduce mutations in DNA molecules (a). The founder member, Activation Induced Deaminase (AID), is a DNA mutator that, after recruitment to the transcribed immunoglobulin gene, deaminates cytosine residues to uracil. The deamination, followed by the recruitment of the DNA repair machinery, results in the mutation and recombination of the antibody genes, thus initiating the antigen-driven antibody diversification processes (b).

AID is a powerful tool to improve the immune response, but its ability to mutate DNA represents a double edged sword: transgenic mice constitutively expressing AID develop cancer (c) and there is increasing evidence linking AID to the onset of mature B-cell lymphomas (d). These tumors arise during the antigen dependent stages of the antibody gene diversification, and are often characterized by chromosomal translocations involving the IgH gene. While such chromosomal aberrations have been long hypothesized to be linked to the antibody gene diversification processes, only recently it has been proven that AID triggers c-myc/IgH translocations (a common trait in Burkitt's lymphomas) in Balb/c mice by targeting both the IgH locus and the c-myc locus. Moreover, expression of AID is needed in order to develop germinal center derived lymphomas in cancer-prone mice.

In addition to the B-cell lineage, AID is able to induce cancer in other experimental settings: ectopic expression of AID in transgenic mice induces cancer, and AID could be involved in the onset of chromosomal translocations specific for prostatic cancer in a prostate cell line.

At the current state of research, the specific processes by which AID can ultimately trigger cancer are not known. AID could induce DNA lesions somehow mimicking those occuring during B-cell development; these lesions could originate from a genome-wide mistargeting; or cells could be affected by changes in the methylation status of mistargeted genes. Indeed, much of the pathological effects of AID might depend on factors and pathways involved in its regulation: inflammation and inflammation-related signaling pathways can trigger expression of AID in B-cells and in other cell types. Unfortunately, very little is known about the crossroad between regulation of AID and its targeting of the DNA.

The main objective of our research is to investigate the role of AID in the onset and progression of human cancer through two converging approaches:

  1. Identification and characterization of molecules and pathways controlling the function of AID: while overexpression of AID induces a generalized increase in mutations, under physiological conditions the primary target for AID is a specific region in the immunoglobulin locus. This suggests the existence of a targeting machinery and the possibility that AID misregulation could lead to DNA lesions and tumorigenesis. During my postdoctoral period at the MRC-LMB, I identified CTNNBL1, a spliceosome-associated molecule, as a specific interactor of AID involved in its targeting (e). Mutations in AID that interfere with the interaction lead to defects both in somatic hypermutation and class switch recombination. While the role of CTNNBL1 has not yet been clarified, its association with the spliceosome is intriguing: this is the first molecule specifically linking the targeting of AID to the mRNA processing machinery.
    To this aim, we use a number of tools, ranging from biochemical and bacterial assays to cellular assays. In particular, DT40 cells - a chicken lymphoma cell line - which allow efficient gene targeting and provide a reliable assay system for AID function, and CH12F3 cells, a murine lymphoma clone in which AID can be induced to trigger IgM to IgA class switch recombination. In these models, we can analyze both the ability of AID to initiate the antibody diversification processes and its role in the mistargeting of somatic mutations and induction of cancer-like c-myc/IgH chromosomal translocations, analogous to those found in Burkitt's lymphoma. The information gathered through this research will be then used in transgenic mice to investigate whether forced expression of AID mutants and AID regulators makes B-cells more/less susceptible to tumorigenesis.
  2. Analysis of human hematopoietic tumors: to assess whether distinct patterns of expression are associated with specific types of cancer and their prognosis, and to test our findings on the regulatory pathways of AID directly on the cancer tissues and thus evaluate their relevance to the biology of cancer. Constitutive expression of AID has been reported in a number of lymphoproliferative malignancies. In some cases, such as in chronic lymphocytic leukemia, AID is, paradoxically, expressed tumors with unmutated immunoglobulin V genes, while it seems absent from the ones with mutated immunoglobulin genes, which have a better prognosis. With AID expression being linked to the prognosis in B-cell lineage tumors, we are investigating whether AID is merely a relic of the developmental stage at the origin of the tumor or it plays an active role in the progression of the cancer. Whichever the answer, we will try to correlate the presence of AID to specific neoplastic subpopulations and to the relative prognosis. This approach will naturally complement the molecular dissection of AID regulatory pathways, as we will be able to test our findings directly on the neoplastic samples and thus evaluate their relevance to the biology of cancer.


  1. Conticello SG: The AID/APOBEC family of nucleic acid mutators. Genome Biol 2008; 9: 229.
  2. Di Noia JM, Neuberger MS: Molecular mechanisms of antibody somatic hypermutation. Annu Rev Biochem 2007; 76: 1-22.
  3. Okazaki IM, Kotani A, Honjo T: Role of AID in tumorigenesis. Adv Immunol 2007; 94: 245-73.
  4. Pérez-Durán P, de Yebenes VG, Ramiro AR: Oncogenic events triggered by AID, the adverse effect of antibody diversification. Carcinogenesis 2007; 28: 2427-33.
  5. Conticello SG, Ganesh K, Xue K, Lu M, Rada C, Neuberger MS: Interaction between antibody-diversification enzyme AID and spliceosome-associated factor CTNNBL1. Mol Cell 2008; 31: 474-84.

Main collaborations

With units within ITT

  • Department of Oncology, Azienda Ospedaliero Universitaria Careggi (AOU Careggi), Firenze
  • Hematology and Transplant Unit, University of Siena

With other Italian and foreign units

  • Medical Research Council, Laboratory of Molecular Biology, Cambridge (UK)


  1. LaRue RS, Andrésdóttir V, Blanchard Y, et al: Guidelines for naming nonprimate APOBEC3 genes and proteins. J Virol 2009; 83: 494-7.
  2. Conticello SG, Langlois MA, Yang Z, Neuberger MS: DNA deamination in immunity: AID in the context of its APOBEC relatives. Adv Immunol 2007; 94: 37-73.
  3. Conticello SG, Thomas CJ, Petersen-Mahrt SK, Neuberger MS: Evolution of the AID/APOBEC family of polynucleotide (deoxy)cytidine deaminases. Mol Biol Evol 2005; 22: 367-77.
  4. Langlois MA, Beale RC, Conticello SG, Neuberger MS: Mutational comparison of the single-domained APOBEC3C and double-domained APOBEC3F/G anti-retroviral cytidine deaminases provides insight into their DNA target site specificities. Nucleic Acids Res 2005; 33: 1913-23.
  5. Conticello SG, Harris RS, Neuberger MS: The vif protein of HIV triggers degradation of the human antiretroviral DNA deaminase APOBEC3G. Curr Biol 2003; 13: 2009-13.
  6. Conticello SG, Kowalsman ND, Jacobsen C, et al: The prodomain of a secreted hydrophobic mini-protein facilitates its export from the endoplasmic reticulum by hitchhiking on sorting receptors. J Biol Chem 2003; 278: 26311-4.
  7. Tcherpakov M, Bronfman FC, Conticello SG, et al: The p75 neurotrophin receptor interacts with multiple MAGE proteins. J Biol Chem 2002; 277: 49101-4.
  8. Conticello SG, Gilad Y, Avidan N, Ben-Asher E, Levy Z, Fainzilber M: Mechanisms for evolving hypervariability: the case of conopeptides. Mol Biol Evol 2001; 18: 120-31.
  9. Jaaro H, Beck G, Conticello SG, Fainzilber M: Evolving better brains: a need for neurotrophins? Trends Neurosci 2001;24: 79-85.