A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas
Tint Lwin, … , Eduardo Sotomayor, Jianguo Tao
Tint Lwin, … , Eduardo Sotomayor, Jianguo Tao
Published October 8, 2013
Citation Information: J Clin Invest. 2013;123(11):4612-4626. https://doi.org/10.1172/JCI64210.
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A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas

Abstract

A dynamic interaction occurs between the lymphoma cell and its microenvironment, 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, clonogenicity, and induction of histone deacetylase 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 cell lines. 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.

Authors

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

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Figure 7

Targeting c-Myc overcomes CAM-DR and cooperates with HDAC6 to regulate stroma-mediated drug resistance.

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Targeting c-Myc overcomes CAM-DR and cooperates with HDAC6 to regulate s...
(A) Lymphoma cells were treated with JQ1 (1 μM) and/or mitoxantrone (0.2 μM) for 48 hours with or without HK cell adhesion as indicated, and apoptosis was analyzed by flow cytometry using Annexin V. (B) Lymphoma cells were treated with JQ1 (1 μM) and/or tubastatin A (1 μM) for 48 hours with or without HK cell adhesion as indicated, and apoptosis was analyzed by flow cytometry using Annexin V. (C) Cell proliferation assay (CCK8) shows that JQ1 and tubastatin A cotreatment synergistically inhibits lymphoma cell growth. Cells were treated with tubastatin A and/or JQ1 as indicated for 48 hours, and CCK8 assay was performed. (B and C) Data are representative of 4 independent experiments (mean ± SD). (D) Stroma-mediated c-Myc/miR-548m/HDAC6 amplification loop drives drug resistance, clonogenic growth, and tumor progression in B cell lymphomas. The stroma-lymphoma interaction induces c-Myc expression and miR-548m downregulation, leading to HDAC6 overexpression, and contributes to lymphoma cell survival, drug resistance, growth, and tumor progression. c-Myc and miR-548m generate a forward-feedback loop to ensure persistently high protein levels of c-Myc and low levels of miR-548m in B cell lymphoma microenvironment.