Aging predisposes B cells to malignancy by activating c-Myc and perturbing the genome and epigenome

Age is the single major risk factor for human cancer; however, naturally occurring cancers are rarely studied in aged animal models. Laboratory mouse strains spontaneously develop cancer with age and some predominantly die from B-cell lymphoma. Here, we uncover how B-cell lymphoma develops as a consequence of the aging immune system. We found that aged B cells undergo clonal expansions driven by genetic and epigenetic changes and established cell and spleen size as early markers of malignant transformation. High-throughput and omics assays of aged B cells and the use of mouse models revealed that c-Myc is a master regulator of B cell size and clonal expansion. A single-cell RNA-seq analysis suggested that clonal B cells originate from age-associated B cells, memory B cells that accumulate during aging. Further studies showed that c-Myc becomes activated in B cells in response to the aging microenvironment. Thus, c-Myc, aging environment, somatic mutations and the epigenome cooperate to give rise to clonal age-accelerated B cells, which we named Myc+ cells. We further show the relevance of this model to aged human B cells in blood and spleen. This study characterized a first mouse model that captures a natural transition of B cells to a prevalent type of cancer during aging.