José P Castro, Anastasia V Shindyapina, Alessandro Barbieri, Kejun Ying, Olga S Strelkova, João A Paulo, Alexander Tyshkovskiy, Rico Meinl, Csaba Kerepesi, Anna P Petrashen, Marco Mariotti, Margarita V Meer, Yan Hu, Alexander Karamyshev, Grigoriy Losyev, Mafalda Galhardo, Elsa Logarinho, Artur A Indzhykulian, Steven P Gygi, John M Sedivy, John P Manis, Vadim N Gladyshev
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引用次数: 0
摘要
虽然癌症是一种与年龄相关的疾病,但人们对衰老过程如何导致癌症进展还不甚了解。在这项研究中,我们揭示了小鼠 B 细胞淋巴瘤是如何在自然老化的系统中发展起来的。我们在此表明,这种恶性肿瘤与年龄相关克隆 B 细胞(ACBC)群有关,而 ACBC 很可能源自年龄相关 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独立于生殖中心进行克隆扩增,并显示出生物年龄的增加。当 ACBC 移植到年轻的受体时,会变得自给自足并支持恶性肿瘤。抑制老龄小鼠的 mTOR 或 c-Myc 可减轻衰老过程中 B 细胞的恶性前变化。虽然小鼠和人类 B 细胞淋巴瘤的病因不同,但转化小鼠 B 细胞的表观遗传学变化与人类 B 细胞淋巴瘤中观察到的变化相似。总之,我们的研究结果描述了衰老过程中癌症通过细胞内在变化和微环境变化自发发展的特点,并提出了预防癌症的干预措施。
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.