Novel Tumor Suppressor Function of Glucocorticoid-Induced TNF Receptor GITR in Multiple Myeloma |
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| Authors: | Yang Liu Phong Quang Esteban Braggio Hai Ngo Gayane Badalian-Very Ludmila Flores Yong Zhang Antonio Sacco Patricia Maiso Abdel Kareem Azab Feda Azab Ruben Carrasco Barrett J. Rollins Aldo M. Roccaro Irene M. Ghobrial |
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| Affiliation: | 1. Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, United States of America.; 2. Department of Medicine, Division of Haematology, Mayo Clinic College of Medicine, Scottsdale, Arizona, United States of America.; Emory University, United States of America, |
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| Abstract: | Glucocorticoid-induced TNF receptor (GITR) plays a crucial role in modulating immune response and inflammation, however the role of GITR in human cancers is poorly understood. In this study, we demonstrated that GITR is inactivated during tumor progression in Multiple Myeloma (MM) through promoter CpG island methylation, mediating gene silencing in primary MM plasma cells and MM cell lines. Restoration of GITR expression in GITR deficient MM cells led to inhibition of MM proliferation in vitro and in vivo and induction of apoptosis. These findings were supported by the presence of induction of p21 and PUMA, two direct downstream targets of p53, together with modulation of NF-κB in GITR-overexpressing MM cells. Moreover, the unbalanced expression of GITR in clonal plasma cells correlated with MM disease progression, poor prognosis and survival. These findings provide novel insights into the pivotal role of GITR in MM pathogenesis and disease progression. |
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