A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas

作者：Lwin Tint; Zhao Xiaohong; Cheng Fengdong; Zhang Xinwei; Huang Andy; Shah Bijal; Zhang Yizhuo; Moscinski Lynn C; Choi Yong Sung; Kozikowski Alan P; Bradner James E; Dalton William S; Sotomayor Eduardo; Tao Jianguo^*

来源：Journal of Clinical Investigation, 2013, 123(11): 4612-4626.

DOI：10.1172/JCI64210

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.

• 出版日期2013-11