Final Report Summary - IMMUNOSWITCH (Switch recombination: a model system for DNA editing and repair in human lymphocytes with relevance for primary immunodeficiency and cancer formation)
The project is aimed at understanding the complex molecular mechanisms involved in programmed DNA editing/repair during immunoglobulin class switch recombination (CSR) and somatic hypermutation (SHM), two important DNA modification processes that required for production of functional antibodies. The project is also aimed at understanding how these processes are related to the development of human diseases, such as immunodeficiency and cancer.
Since the project started five years ago, we have successfully built an international, dynamic research team, which currently consists of a senior scientist (the PI), one technician, five postdoctoral fellows and four PhD students. Our past and current team members are young scientists recruited from six European countries (Sweden, Germany, Italy, Portugal, Greece and Cyprus) as well as from USA, India and China, with background in medicine, cancer biology, immunology, bioinformatics evolutional biology and molecular biology.
By studying the immunoglobulin CSR pattern in B-lymphocytes from patients with inborn errors in DNA repair genes, we have demonstrated that Cernunnos (also called XLF), in additional to its role in V(D)J recombination, is also involved in the non-homologous end-joining (NHEJ) pathway during CSR. Furthermore, we have discovered a “cross-talk” between the NHEJ and the cohesin pathways during CSR. As both the NHEJ machinery and the coheisn complex are crucial for basic cellular mechanisms, i.e. DNA double strand break repair and segregation of chromosomes during mitosis respectively, our finding is not only improving our knowledge about immunoglobulin gene diversification, but also our understanding on the general DNA repair/modification machinery in mammalian cells.
We have furthermore shown that BRCA1, a well known tumor suppressor for breast and ovarian cancers, seem to play an important role in repairing DSBs generated during CSR by promoting the c-NHEJ pathway. This may not only provide a general mechanism underlying BRCA1’s function in maintaining genome stability and tumor suppression, but also point to a previously unrecognized role of BRCA1 in development of B cell malignancies.
Using a genome-wide association study, we have identified a new gene (IFIH1) that is associated with the development of the most common form of primary immunodeficiency, IgA deficiency. By genome-wide linkage analysis, we have also identified two novel molecular defects, LRBA- and RAC2- deficiency, underlying another form of primary immunodeficiency, common variable immunodeficiency. Both groups of patients suffer from recurrent infections as well as autoimmune symptoms and the identification of molecular basis of these disorders might help the diagnosis as well as development of new therapies for these patients.
By applying the next generation sequencing technologies, we have identified mutations in a number of DNA repair genes that have been associated with immunoglobulin gene diversifications, especially the CSR process, in mature B cell lymphoma samples. We have furthermore provided evidence that the B cell mutator, AID, is recruited by B cell super enhancers, to generate “off-targeted” mutations in the genome, which might contribute to the development of B cell lymphoma. The connections among DNA repair defects, genome instability, aberrant CSR, immunodeficiency and B cell lymphomagenesis are further strengthened by our study, which shed lights on the complex pathogenesis of mature B cell lymphomas, especially the most aggressive form, diffuse large B cell lymphomas. The study may also help to develop new strategies for personalized, targeted-therapy in patients with this form of lymphomas.
Since the project started five years ago, we have successfully built an international, dynamic research team, which currently consists of a senior scientist (the PI), one technician, five postdoctoral fellows and four PhD students. Our past and current team members are young scientists recruited from six European countries (Sweden, Germany, Italy, Portugal, Greece and Cyprus) as well as from USA, India and China, with background in medicine, cancer biology, immunology, bioinformatics evolutional biology and molecular biology.
By studying the immunoglobulin CSR pattern in B-lymphocytes from patients with inborn errors in DNA repair genes, we have demonstrated that Cernunnos (also called XLF), in additional to its role in V(D)J recombination, is also involved in the non-homologous end-joining (NHEJ) pathway during CSR. Furthermore, we have discovered a “cross-talk” between the NHEJ and the cohesin pathways during CSR. As both the NHEJ machinery and the coheisn complex are crucial for basic cellular mechanisms, i.e. DNA double strand break repair and segregation of chromosomes during mitosis respectively, our finding is not only improving our knowledge about immunoglobulin gene diversification, but also our understanding on the general DNA repair/modification machinery in mammalian cells.
We have furthermore shown that BRCA1, a well known tumor suppressor for breast and ovarian cancers, seem to play an important role in repairing DSBs generated during CSR by promoting the c-NHEJ pathway. This may not only provide a general mechanism underlying BRCA1’s function in maintaining genome stability and tumor suppression, but also point to a previously unrecognized role of BRCA1 in development of B cell malignancies.
Using a genome-wide association study, we have identified a new gene (IFIH1) that is associated with the development of the most common form of primary immunodeficiency, IgA deficiency. By genome-wide linkage analysis, we have also identified two novel molecular defects, LRBA- and RAC2- deficiency, underlying another form of primary immunodeficiency, common variable immunodeficiency. Both groups of patients suffer from recurrent infections as well as autoimmune symptoms and the identification of molecular basis of these disorders might help the diagnosis as well as development of new therapies for these patients.
By applying the next generation sequencing technologies, we have identified mutations in a number of DNA repair genes that have been associated with immunoglobulin gene diversifications, especially the CSR process, in mature B cell lymphoma samples. We have furthermore provided evidence that the B cell mutator, AID, is recruited by B cell super enhancers, to generate “off-targeted” mutations in the genome, which might contribute to the development of B cell lymphoma. The connections among DNA repair defects, genome instability, aberrant CSR, immunodeficiency and B cell lymphomagenesis are further strengthened by our study, which shed lights on the complex pathogenesis of mature B cell lymphomas, especially the most aggressive form, diffuse large B cell lymphomas. The study may also help to develop new strategies for personalized, targeted-therapy in patients with this form of lymphomas.