Transposons and γ-retroviruses have been efficiently used as insertional mutagens in different tissues to identify molecular culprits of cancer. However, these systems are characterized by recurring integrations that accumulate in tumor cells and that hamper the identification of early cancer-driving events among bystander and progression-related events. We developed an insertional mutagenesis platform based on lentiviral vectors (LVVs) by which we could efficiently induce hepatocellular carcinoma (HCC) in three different mouse models. By virtue of the LVV's replication-deficient nature and broad genome-wide integration pattern, LVV-based insertional mutagenesis allowed identification of four previously unknown liver cancer-associated genes from a limited number of integrations. We validated the oncogenic potential of all the identified genes in vivo, with different levels of penetrance. The newly identified genes are likely to play a role in human cancer because they are upregulated, amplified and/or deleted in human HCCs and can predict clinical outcomes of patients.
The advent of chimeric antigen receptor (CAR) T-cells has revolutionized the treatment landscape for hematologic malignancies, and emerging evidence suggests their potential in autoimmune diseases (AIDs). This article examines the early successes and future implications of B-cell-targeting CAR T-cell therapy in AIDs. Initial applications, particularly in refractory systemic lupus erythematosus (SLE), have demonstrated significant and durable clinical remissions, with accompanying evaluation of the immune system suggesting a so-called "reset" of innate inflammation and adaptive autoimmunity.
Collections of insertional mutants have been instrumental for characterizing the functional relevance of genes in different model organisms, including Arabidopsis (Arabidopsis thaliana). However, mutations may often result in subtle phenotypes, rendering it difficult to pinpoint the function of a knocked-out gene. Here, we present a data-integrative modeling approach that enables predicting the effects of mutations on metabolic traits and plant growth.
Department of Medical Genetics, University of British Columbia, Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, BC, V6T 1Z3, Canada. Electronic address:
The Mitf transcription factor is a critical regulator of the melanocyte lineage and eye development. Mitf activity in different cell types is controlled in part by ten alternative promoters and their resulting isoforms. A useful tool for melanocyte-based research, Mitf-cre was designed to express Cre from the Mitf-M promoter, which is melanocyte specific.
Adeno-associated viral (AAV) vector-mediated gene therapy has emerged as a promising alternative to liver transplantation for monogenic metabolic hepatic diseases. AAVs are non-integrative vectors that are maintained primarily as episomes in quiescent cells like adult hepatocytes. This quality, while advantageous from a safety perspective due to a decreased risk of insertional mutagenesis, becomes a disadvantage when treating dividing cells, as it inevitably leads to the loss of the therapeutic genome.
The human genome is packaged within a three-dimensional (3D) nucleus and organized into structural units known as compartments, topologically associating domains (TADs), and loops. TAD boundaries, separating adjacent TADs, have been found to be well conserved across mammalian species and more evolutionarily constrained than TADs themselves. Recent studies show that structural variants (SVs) can modify 3D genomes through the disruption of TADs, which play an essential role in insulating genes from outside regulatory elements' aberrant regulation.
