Role of TNFSF9 in germinal centre B cells and lymphoma formation

Members of the TNF superfamily play critical regulatory functions in hematopoietic cell lineage and function. Tnfsf9 is expressed in various hematopoietic cells, including B cells. Its receptor CD137, also known as 4-1BB, has been characterised and studied in the context of T cell activation and cancer immunotherapy. Loss of Tnfsf9 is recurrently found in human germinal centre (GC) B cell derived lymphomas and animals lacking Tnfsf9 develop B cell lymphomas. The use of genetically engineered mouse models may help to understand better the biology and function of Tnfsf9 in physiology and cancer. Here, we discover that animals completely deficient for Tnfsf9 display early in life enlarged lymph nodes and spleen, accompanied by spontaneous formation of large GCs. In addition, we investigate in a B cell specific manner the effects of Tnfsf9 loss and report a similar phenotype of spontaneous GCs. Protein microarray analysis of the sera of these mice shows the presence of both IgM and IgG autoantibodies, accompanied by immunoglobulin deposits in kidneys later in life. However, Tnfsf9 deficient animals do not show signs of overt autoimmune mediated pathology; they develop GC B-cell derived lymphomas with 100% penetrance as they age. We show that B cells deficient for Tnfsf9 display increased survival in vitro, and that this phenotype is accompanied by elevated Bcl-2 and Bcl-xL expression. Mechanistically loss of Tnfsf9 increases the activity of the alternative NF-kB signalling pathway upon BCR activation, by allowing increased nuclear translocation of p52. Our findings have implications for the understanding of B cell survival through the modulation of signals emanating from the BCR, and we report here a potential novel role of Tnfsf9 in linking BCR signalling and the alternative NF-kB pathway

RAC1(P29S) Induces a Mesenchymal Phenotypic Switch via Serum Response Factor to Promote Melanoma Development and Therapy Resistance

RAC1 P29 is the third most commonly mutated codon in human cutaneous melanoma, after BRAF V600 and NRAS Q61. Here, we study the role of RAC1P29S in melanoma development and reveal that RAC1P29S activates PAK, AKT, and a gene expression program initiated by the SRF/MRTF transcriptional pathway, which results in a melanocytic to mesenchymal phenotypic switch. Mice with ubiquitous expression of RAC1P29S from the endogenous locus develop lymphoma. When expressed only in melanocytes, RAC1P29S cooperates with oncogenic BRAF or with NF1-loss to promote tumorigenesis. RAC1P29S also drives resistance to BRAF inhibitors, which is reversed by SRF/MRTF inhibitors. These findings establish RAC1P29S as a promoter of melanoma initiation and mediator of therapy resistance, while identifying SRF/MRTF as a potential therapeutic target

Drug-induced liver injury: a comprehensive review

Drug-induced liver injury (DILI) remains a challenge in clinical practice and is still a diagnosis of exclusion. Although it has a low incidence amongst the general population, DILI accounts for most cases of acute liver failure with a fatality rate of up to 50%. While multiple mechanisms of DILI have been postulated, there is no clear causal relationship between drugs, risk factors and mechanisms of DILI. Current best practice relies on a combination of high clinical suspicion, thorough clinical history of risk factors and timeline, and extensive hepatological investigations as supported by the international Roussel Uclaf Causality Assessment Method criteria, the latter considered a key diagnostic algorithm for DILI. This review focuses on DILI classification, risk factors, clinical evaluation, future biomarkers and management, with the aim of facilitating physicians to correctly identify DILI early in presentation