A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas
A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas
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DOI：
10.1172/jci64210
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发表时间：
2013-11-01
影响因子：
15.9
通讯作者：
Tao, Jianguo
中科院分区：
文献类型：
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作者：
Lwin, Tint;Zhao, Xiaohong;Tao, Jianguo
淋巴瘤细胞和它的微生物之间发生动态的相互作用，每一个都深刻地影响着另一个的行为。在这里，使用克隆共培养生长系统和异种移植小鼠模型，我们证明了套细胞淋巴瘤（MCL）和其他非霍奇金淋巴瘤细胞与淋巴瘤基质细胞的粘附赋予耐药性，供体性和组蛋白D.乙酰化酶6（HDAC 6）的诱导。此外，基质触发了c-Myc/miR-548 m前馈环，将持续的c-Myc激活、miR-548 m下调和随后的HDAC 6上调与淋巴瘤细胞系、原发性MCL和其他B细胞淋巴瘤犬中基质介导的细胞存活和淋巴瘤进展联系起来。单独使用HDAC 6选择性抑制剂或与c-Myc抑制剂协同治疗增强了细胞死亡，消除了细胞粘附介导的耐药性，并抑制了离体和体内的克隆形成和淋巴瘤生长。总之，这些数据表明淋巴瘤微环境中的淋巴瘤-基质相互作用通过遗传和表观遗传调节直接影响淋巴瘤的生物学，HDAC 6和c-Myc是潜在的治疗靶点。
A dynamic interaction occurs between the lymphoma cell and its microenvironxnent, with each profoundly influencing the behavior of the other. Here, using a clonogenic coculture growth system and a xenograft mouse model, we demonstrated that adhesion of mantle cell lymphoma (MCL) and other non-Hodgkin lymphoma cells to lymphoma stromal cells confers drug resistance, donogenicity, and induction of histone d.eacetylase 6 (HDAC6). Furthermore, stroma triggered a c-Myc/miR-548m feed-forward loop, linking sustained c-Myc activation, miR-548m downregulation, and subsequent HDAC6 upregulation and stroma-mediated cell survival and lymphoma progression in lymphoma cell lines, primary MCL and other B cell lymphoma canines. Treatment with an HDAC6-selective inhibitor alone or in synergy with a c-Myc inhibitor enhanced cell death, abolished cell adhesion-mediated drug resistance, and suppressed clonogenicity and lymphoma growth ex vivo and in vivo. Together, these data suggest that the lymphoma-stroma interaction in the lymphoma microenvironment directly impacts the biology of lymphoma through genetic and epigenetic regulation, with HDAC6 and c-Myc as potential therapeutic targets.