Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
i3S, Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.
Nat Aging. 2024 Oct;4(10):1403-1417. doi: 10.1038/s43587-024-00671-7. Epub 2024 Aug 8.
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.
尽管癌症是一种与年龄相关的疾病，但衰老过程如何促进癌症的发展还不是很清楚。在这项研究中，我们揭示了小鼠 B 细胞淋巴瘤如何作为自然衰老系统的结果而发展。我们在这里表明，这种恶性肿瘤与年龄相关的克隆 B 细胞（ACBC）群体有关，该群体可能起源于年龄相关的 B 细胞。在 c-Myc 激活、启动子超甲基化和体细胞突变的驱动下，IgM ACBC 独立于生发中心克隆性扩增，并表现出生物年龄的增加。ACBC 变得自给自足，并在转移到年轻受者时支持恶性肿瘤。在老年小鼠中抑制 mTOR 或 c-Myc 可减轻衰老过程中 B 细胞的癌前变化。尽管小鼠和人类 B 细胞淋巴瘤的病因被认为是不同的，但在转化的小鼠 B 细胞中观察到的表观遗传变化在人类 B 细胞淋巴瘤中更为丰富。总之，我们的研究结果通过细胞内和微环境的变化描述了衰老过程中癌症的自发进展，并提出了预防癌症的干预措施。
