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Mol Cancer Res. 2017 Dec;15(12):1733-1740. doi: 10.1158/1541-7786.MCR-17-0315. Epub 2017 Aug 29.

The Influential Role of BCL2 Family Members in Synovial Sarcomagenesis.

Author information

1
Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, Utah.
2
Department of Oncological Sciences, University of Utah School of Medicine, Salt Lake City, Utah.
3
Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah.
4
Center for Quantitative Cancer Imaging, University of Utah School of Medicine, Salt Lake City, Utah.
5
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah.
6
Department of Radiology and Imaging Sciences, University of Utah School of Medicine, Salt Lake City, Utah.
7
Department of Genetic Epidemiology, University of Utah School of Medicine, Salt Lake City, Utah.
8
Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia.
9
Department of Orthopaedics, University of Utah School of Medicine, Salt Lake City, Utah. kevin.jones@hci.utah.edu.

Abstract

Synovial sarcomas are deadly soft tissue malignancies associated with t(X;18) balanced chromosomal translocations. Expression of the apoptotic regulator BCL2 is prominent in synovial sarcomas and has prompted the hypothesis that synovial sarcomagenesis may depend on it. Herein, it is demonstrated that Bcl2 overexpression enhances synovial sarcomagenesis in an animal model. Furthermore, we determined increased familial clustering of human synovial sarcoma patients with victims of other BCL2-associated malignancies in the Utah Population Database. Conditional genetic disruption of Bcl2 in mice also led to reduced sarcomagenesis. Pharmacologic inhibition specific to BCL2 had no demonstrable efficacy against human synovial sarcoma cell lines or mouse tumors. However, targeting BCLxL in human and mouse synovial sarcoma with the small molecule BH3 domain inhibitor, BXI-72, achieved significant cytoreduction and increased apoptotic signaling. Thus, the contributory role of BCL2 in synovial sarcomagenesis does not appear to render it as a therapeutic target, but mitochondrial antiapoptotic BCL2 family members may be.Implications: The association of BCL2 expression with synovial sarcoma is found to fit with a subtle, but significant, impact of its enhanced presence or absence during early tumorigenesis. However, specific pharmacologic inhibition of BCL2 does not demonstrate a persistent dependence in fully developed tumors. Conversely, inhibition of the BCL2 family member BCLxL resulted in nanomolar potency against human synovial sarcoma cell lines and 50% tumor reduction in a genetically engineered mouse model. Mol Cancer Res; 15(12); 1733-40. ©2017 AACR.

PMID:
28851813
PMCID:
PMC5816685
DOI:
10.1158/1541-7786.MCR-17-0315
[Indexed for MEDLINE]
Free PMC Article

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