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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Research Article Oncology

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 1

Cell adhesion to stromal cells (HK cells) induces HDAC6 expression and downregulation of miR-548m in MCL and other B cell lymphoma cell lines and primary cells.

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Cell adhesion to stromal cells (HK cells) induces HDAC6 expression and d...
(A) Heat map showing downregulation of miR-548m/miR-548f/miR-548h expression after lymphoma cells adhered to HK cells for 24 hours, as measured by miRNA array. Sus, cells in suspension; HK-Ad, cells after adhesion to HK cells. (B and C) Cell adhesion induced changes of (B) miR-548m and (C) HDAC6 expression in SUDHL-4, HBL-2, and Jeko-1 lymphoma cells. Lymphoma cells in suspension adhered to the preestablished monolayer of HK cells or with a confluent HK monolayer but separated by Transwell inserts were treated for 24 hours (Transwell). The lymphoma cells were collected, and miR-548m and HDAC6 protein were analyzed by TaqMan microRNA qRT-PCR and Western blot. *P < 0.05; **P > 0.05. (D and E) Cell adhesion–induced changes of (D) miR-548m and (E) HDAC6 expression in primary lymphoma cells. DLBCL, diffuse large B cell lymphoma; FCL, follicular lymphoma. (F) Cell adhesion to bone marrow stromal cells (HS-5 cells) induced changes of miR-548m and HDAC6 expression in SUDHL-4 and HBL-2 cells. *P < 0.05. Results are representative of at least 4 experiments (mean ± SD). (C and E) Thin white lines were used to separate lanes run on different gels.