Abstract：
Epidemiological evidence supports an association between cow\'s milk consumption and the risk of diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma worldwide. This narrative review intends to elucidate the potential impact of milk-related agents, predominantly milk-derived exosomes (MDEs) and their microRNAs (miRs) in lymphomagenesis. Upregulation of PI3K-AKT-mTORC1 signaling is a common feature of DLBCL. Increased expression of B cell lymphoma 6 (BCL6) and suppression of B lymphocyte-induced maturation protein 1 (BLIMP1)/PR domain-containing protein 1 (PRDM1) are crucial pathological deviations in DLBCL. Translational evidence indicates that during the breastfeeding period, human MDE miRs support B cell proliferation via epigenetic upregulation of BCL6 (via miR-148a-3p-mediated suppression of DNA methyltransferase 1 (DNMT1) and miR-155-5p/miR-29b-5p-mediated suppression of activation-induced cytidine deaminase (AICDA) and suppression of BLIMP1 (via MDE let-7-5p/miR-125b-5p-targeting of PRDM1). After weaning with the physiological termination of MDE miR signaling, the infant\'s BCL6 expression and B cell proliferation declines, whereas BLIMP1-mediated B cell maturation for adequate own antibody production rises. Because human and bovine MDE miRs share identical nucleotide sequences, the consumption of pasteurized cow\'s milk in adults with the continued transfer of bioactive bovine MDE miRs may de-differentiate B cells back to the neonatal \"proliferation-dominated\" B cell phenotype maintaining an increased BLC6/BLIMP1 ratio. Persistent milk-induced epigenetic dysregulation of BCL6 and BLIMP1 expression may thus represent a novel driving mechanism in B cell lymphomagenesis. Bovine MDEs and their miR cargo have to be considered potential pathogens that should be removed from the human food chain.
摘要：
流行病学证据支持牛奶消费与弥漫性大B细胞淋巴瘤（DLBCL）风险之间的关联。全球最常见的非霍奇金淋巴瘤。这篇叙述性综述旨在阐明牛奶相关药物的潜在影响，主要是乳源外泌体（MDE）和它们的microRNAs（miRs）在淋巴发生。PI3K-AKT-mTORC1信号传导的上调是DLBCL的共同特征。B细胞淋巴瘤6（BCL6）的表达增加和B淋巴细胞诱导的成熟蛋白1（BLIMP1）/含PR结构域的蛋白1（PRDM1）的抑制是DLBCL的关键病理偏差。转化证据表明，在母乳喂养期间，人MDEmiRs通过表观遗传上调BCL6(通过miR-148a-3p介导的DNA甲基转移酶1(DNMT1)和miR-155-5p/miR-29b-5p介导的活化诱导胞苷脱氨酶(AICDA)的抑制和BLIMP1的抑制(通过MDElet-7-5p/miR-125DM1靶向)来支持B细胞增殖。断奶后随着MDEmiR信号的生理终止，婴儿的BCL6表达和B细胞增殖下降，而BLIMP1介导的B细胞成熟增加了足够的自身抗体生产。因为人和牛MDEmiRs共享相同的核苷酸序列，在继续转移生物活性牛MDEmiRs的情况下，成人食用巴氏灭菌的牛奶可能会使B细胞去分化回新生儿“增殖主导”的B细胞表型，并保持BLC6/BLIMP1比值增加。因此，持续的牛奶诱导的BCL6和BLIMP1表达的表观遗传失调可能代表了B细胞淋巴发生的新驱动机制。牛MDE及其miR货物必须被认为是应该从人类食物链中去除的潜在病原体。
