Age-associated clonal B cells drive B cell lymphoma in mice.

Although cancer is an age-related disease, how the processes of aging contribute to cancer progression is not well understood. In this study, we uncovered how mouse B cell lymphoma develops as a consequence of a naturally aged system. We show here that this malignancy is associated with an age-associated clonal B cell (ACBC) population that likely originates from age-associated B cells. Driven by c-Myc activation, promoter hypermethylation and somatic mutations, IgM+ ACBCs clonally expand independently of germinal centers and show increased biological age. ACBCs become self-sufficient and support malignancy when transferred into young recipients. Inhibition of mTOR or c-Myc in old mice attenuates pre-malignant changes in B cells during aging. Although the etiology of mouse and human B cell lymphomas is considered distinct, epigenetic changes in transformed mouse B cells are enriched for changes observed in human B cell lymphomas. Together, our findings characterize the spontaneous progression of cancer during aging through both cell-intrinsic and microenvironmental changes and suggest interventions for its prevention.

nf-encyclopedia: A Cloud-Ready Pipeline for Chromatogram Library Data-Independent Acquisition Proteomics Workflows.

Data-independent acquisition (DIA) mass spectrometry methods provide systematic and comprehensive quantification of the proteome; yet, relatively few open-source tools are available to analyze DIA proteomics experiments. Fewer still are tools that can leverage gas phase fractionated (GPF) chromatogram libraries to enhance the detection and quantification of peptides in these experiments. Here, we present nf-encyclopedia, an open-source NextFlow pipeline that connects three open-source tools, MSConvert, EncyclopeDIA, and MSstats, to analyze DIA proteomics experiments with or without chromatogram libraries. We demonstrate that nf-encyclopedia is reproducible when run on either a cloud platform or a local workstation and provides robust peptide and protein quantification. Additionally, we found that MSstats enhances protein-level quantitative performance over EncyclopeDIA alone. Finally, we benchmarked the ability of nf-encyclopedia to scale to large experiments in the cloud by leveraging the parallelization of compute resources. The nf-encyclopedia pipeline is available under a permissive Apache 2.0 license; run it on your desktop, cluster, or in the cloud: https://github.com/TalusBio/nf-encyclopedia.

A Safer Path to Cellular Rejuvenation: Endogenous Oct4 Activation via CRISPR/dCas9 in Progeria Mouse Models.

A recent study in Aging Cell showed that transcriptional activation of endogenous Oct4 using the CRISPR/dCas9 activator system is sufficient for cellular rejuvenation and extending the lifespan of a progeria mouse model. Although transient expression of reprogramming factors Oct4, Sox2, Klf4, and c-Myc (OSKM) has been shown to ameliorate age-related phenotypes in vivo, oncogenic risk, for example, from c-Myc, has raised safety concerns for its use in therapeutics. The authors demonstrated that transient activation of endogenous Oct4 expression restored age-related epigenetic patterns, suppressed expression of mutant progerin, and reduced vascular pathological features associated with the disease. At the same time, the transient Oct4 overexpression resulted in lower incidence of cancer transformation compared with constituent OSKM overexpression. Successful activation of endogenous Oct4 by CRISPR/dCas9 paves the way for novel therapeutic approaches for the treatment of progeria and age-related diseases, with potential implications for the broader field of cellular reprogramming-based rejuvenation.