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

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

doi:10.1172/JCI64210

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

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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55 Scopus citations

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.

Original language	English (US)
Pages (from-to)	4612-4626
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	123
Issue number	11
DOIs	https://doi.org/10.1172/JCI64210
State	Published - Nov 1 2013
Externally published	Yes

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Medicine(all)

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Lwin, T., Zhao, X., Cheng, F., Zhang, X., Huang, A., Shah, B., Zhang, Y., Moscinski, L. C., Choi, Y. S., Kozikowski, A. P., Bradner, J. E., Dalton, W. S., Sotomayor, E., & Tao, J. (2013). A microenvironment-mediated c-Myc/miR-548m/HDAC6 amplification loop in non-Hodgkin B cell lymphomas. Journal of Clinical Investigation, 123(11), 4612-4626. https://doi.org/10.1172/JCI64210

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title = "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.",

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

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AU - Lwin, Tint

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AU - Cheng, Fengdong

AU - Zhang, Xinwei

AU - Huang, Andy

AU - Shah, Bijal

AU - Zhang, Yizhuo

AU - Moscinski, Lynn C.

AU - Choi, Yong Sung

AU - Kozikowski, Alan P.

AU - Bradner, James E.

AU - Dalton, William S.

AU - Sotomayor, Eduardo

AU - Tao, Jianguo

PY - 2013/11/1

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N2 - 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.

AB - 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.

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

Abstract

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