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

被引：67

作者：

Lwin, Tint ^{[1
,2
]}

Zhao, Xiaohong ^{[1
,2
]}

Cheng, Fengdong ^{[2
,3
,4
]}

Zhang, Xinwei ^{[5
]}

Huang, Andy ^{[1
,2
]}

Shah, Bijal ^{[2
,3
,4
]}

Zhang, Yizhuo ^{[5
]}

Moscinski, Lynn C. ^{[1
,2
]}

Choi, Yong Sung ^{[6
]}

Kozikowski, Alan P. ^{[7
]}

Bradner, James E. ^{[8
]}

Dalton, William S. ^{[2
,3
,4
]}

Sotomayor, Eduardo ^{[2
,3
,4
]}

Tao, Jianguo ^{[1
,2
]}

机构：

[1] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Dept Hematopathol & Lab Med, Tampa, FL 33613 USA

[2] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Expt Therapeut Program, Tampa, FL 33613 USA

[3] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Dept Malignant Hematol, Tampa, FL 33613 USA

[4] Univ S Florida, H Lee Moffitt Canc Ctr & Res Inst, Dept Immunol, Tampa, FL 33613 USA

[5] Tianjin Canc Hosp, Dept Immunol & Hematol, Tianjin, Peoples R China

[6] Alton Ochsner Med Fdn & Ochsner Clin, Lab Cellular Immunol, New Orleans, LA USA

[7] Univ Illinois, Drug Discovery Program, Dept Med Chem & Pharmacognosy, Chicago, IL USA

[8] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2013年 / 123卷 / 11期

关键词：

FOLLICULAR DENDRITIC CELLS; MARROW STROMAL CELLS; MANTLE-CELL; DOWN-REGULATION; CHAPERONE FUNCTION; DRUG-RESISTANCE; UP-REGULATION; C-MYC; EXPRESSION; INHIBITOR;

D O I：

10.1172/JCI64210

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：4612 / 4626

页数：15

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