Stefano Casola, 2006
Career Development Award Project Title
“The role of the B cell antigen receptor in the pathogenesis of B cell lymphomas. Lessons from mouse models”, 2006
Who he is
Stefano Casola is a molecular oncologist specialized in the study of the processes controlling B lymphocyte differentiation and malignant B cell transformation.
After receiving his MD and PhD degrees from the University Federico II of Naples, he joined the Institute of Genetics at the University of Cologne in Germany as post-doctoral fellow, working in the group of immunologist K. Rajewsky. Here he developed novel approaches to modulate in vivo gene expression in a cell-type and stage specific fashion using Cre-loxP technolgy. In particular, he applied conditional gene targeting to study gene function in B-lymphocytes partecipating to the germinal center reaction and established the role of Epstein Barr-Virus encoded proteins LMP1 and LMP2A in the development of malignant lymphomas, originating from germinal center B cells.
After his postdoc experience, Casola moved on to the Harvard Medical School in Boston becoming Junior Investigator at the CBR Institute for Biomedical Research and Instructor in the Department of Pathology. In 2006, he returned to Italy thanks to the Armenise Harvard Career Development Award and to the AIRC Institute of Molecular Biology (IFOM), to lead his own laboratory in Milan.
There he set up the research program on Genetics of B cells and lymphomas, dedicated to the study of immune cells and their malignant cancerous counterparts giving rise to B cell lymphomas.
What he does
His lab studies mechanisms controlling B cell immunity and lymphomas, common forms of blood cancers, often resulting from an aberrant response of the immune system. When B cells recognize foreign invading pathogens including viruses and bacteria, they produce antibodies to fight them. This process relies on the rapid massive proliferation of initially rare pathogen-specific B cells, which is accompanied by genetic rearrangements that ensure lymphocytes to produce antibodies with greater neutralizing activity. Alterations in this highly coordinated process lead to the development of malignant B cell lymphomas. Casola’s research team has also a long-standing interest and advanced expertise in understanding the genetic and epigenetic mechanisms controlling B-cell immune responses.
A major focus of his studies is determining the role of the B cell receptor (BCR) expressed by B-lymphocytes and the majority of B cell lymphomas in coordinating proliferation, survival and differentiation of these cells.
News from the Lab
The lab has recently gained visibility for its studies on the role of the BCR in B cell lymphomas. By integrating genetically engineered mouse models with analyses of human lymphoma specimens, we have dissected the mechanisms through which the BCR enhances the competitive fitness of malignant B cells. These studies have also provided insight into how lymphoma variants evade BCR dependence through the activation of specific molecular pathways and the acquisition of defined genetic alterations.
These findings have important clinical implications, highlighting the need to incorporate diagnostic assessment of BCR status to optimally stratify patients for BCR-targeted therapies, while sparing others from unnecessary toxicity.
Extending these findings to highly aggressive, life-threatening MYC- and BCL2-rearranged high-grade B cell lymphomas, we uncovered novel mechanisms underlying their origin. In particular, we linked BCR silencing in these tumors to the reactivation of the RAG recombinase machinery, normally silenced in mature B cells, thereby promoting genomic instability, driving disease-associated chromosomal rearrangements, and enhancing tumor aggressiveness. This work provides a foundation for the identification of therapeutically targetable vulnerabilities in BCR-silenced aggressive B cell lymphomas.
