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Inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1/INI1 protein in a molecular subset of atypical teratoid/rhabdoid tumors.
Pathak, Rajiv; Zin, Francesca; Thomas, Christian; Bens, Susanne; Gayden, Tenzin; Karamchandani, Jason; Dudley, Roy W; Nemes, Karolina; Johann, Pascal D; Oyen, Florian; Kordes, Uwe; Jabado, Nada; Siebert, Reiner; Paulus, Werner; Kool, Marcel; Frühwald, Michael C; Albrecht, Steffen; Kalpana, Ganjam V; Hasselblatt, Martin.
Affiliation
  • Pathak R; Departments of Genetics and Microbiology and Immunology, Albert Einstein College of Medicine, New York, NY, 10461, USA.
  • Zin F; Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany.
  • Thomas C; Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany.
  • Bens S; Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm, Germany.
  • Gayden T; Department of Human Genetics, McGill University, Montreal, Canada.
  • Karamchandani J; Department of Pathology, Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
  • Dudley RW; Division of Neurosurgery, Department of Pediatric Surgery, Montreal Children's Hospital, McGill University, Montreal, QC, Canada.
  • Nemes K; Paediatric and Adolescent Medicine, Swabian Childrens' Cancer Center, University Childrens' Hospital Medical Center Augsburg and EU-RHAB Registry, Augsburg, Germany.
  • Johann PD; Paediatric and Adolescent Medicine, Swabian Childrens' Cancer Center, University Childrens' Hospital Medical Center Augsburg and EU-RHAB Registry, Augsburg, Germany.
  • Oyen F; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  • Kordes U; Division of Paediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Jabado N; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Siebert R; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
  • Paulus W; Division of Hematology/Oncology, McGill University, Montreal, QC, Canada.
  • Kool M; Institute of Human Genetics, Ulm University & Ulm University Medical Center, Ulm, Germany.
  • Frühwald MC; Institute of Neuropathology, University Hospital Münster, Pottkamp 2, 48149, Münster, Germany.
  • Albrecht S; Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
  • Kalpana GV; Division of Paediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
  • Hasselblatt M; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
Acta Neuropathol ; 142(2): 361-374, 2021 08.
Article in En | MEDLINE | ID: mdl-34003336
Loss of nuclear SMARCB1 (INI1/hSNF5/BAF47) protein expression due to biallelic mutations of the SMARCB1 tumor suppressor gene is a hallmark of atypical teratoid/rhabdoid tumors (ATRT), but the presence of cytoplasmic SMARCB1 protein in these tumors has not yet been described. In a series of 102 primary ATRT, distinct cytoplasmic SMARCB1 staining on immunohistochemistry was encountered in 19 cases (19%) and was highly over-represented in cases showing pathogenic sequence variants leading to truncation or mutation of the C-terminal part of SMARCB1 (15/19 vs. 4/83; Chi-square: 56.04, p = 1.0E-10) and, related to this, in tumors of the molecular subgroup ATRT-TYR (16/36 vs. 3/66; Chi-square: 24.47, p = 7.6E-7). Previous reports have indicated that while SMARCB1 lacks a bona fide nuclear localization signal, it harbors a masked nuclear export signal (NES) and that truncation of the C-terminal region results in unmasking of this NES leading to cytoplasmic localization. To determine if cytoplasmic localization found in ATRT is due to unmasking of NES, we generated GFP fusions of one of the SMARCB1 truncating mutations (p.Q318X) found in the tumors along with a p.L266A mutation, which was shown to disrupt the interaction of SMARCB1-NES with exportin-1. We found that while the GFP-SMARCB1(Q318X) mutant localized to the cytoplasm, the double mutant GFP-SMARCB1(Q318X;L266A) localized to the nucleus, confirming NES requirement for cytoplasmic localization. Furthermore, cytoplasmic SMARCB1(Q318X) was unable to cause senescence as determined by morphological observations and by senescence-associated ß-galactosidase assay, while nuclear SMARCB1(Q318X;L266A) mutant regained this function. Selinexor, a selective exportin-1 inhibitor, was effective in inhibiting the nuclear export of SMARCB1(Q318X) and caused rapid cell death in rhabdoid tumor cells. In conclusion, inhibition of nuclear export restores nuclear localization and residual tumor suppressor function of truncated SMARCB1. Therapies aimed at preventing nuclear export of mutant SMARCB1 protein may represent a promising targeted therapy in ATRT harboring truncating C-terminal SMARCB1 mutations.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Rhabdoid Tumor / Neoplasm, Residual / Active Transport, Cell Nucleus / SMARCB1 Protein Limits: Child, preschool / Female / Humans / Infant / Male Language: En Journal: Acta Neuropathol Year: 2021 Document type: Article Affiliation country: Estados Unidos Country of publication: Alemania

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Rhabdoid Tumor / Neoplasm, Residual / Active Transport, Cell Nucleus / SMARCB1 Protein Limits: Child, preschool / Female / Humans / Infant / Male Language: En Journal: Acta Neuropathol Year: 2021 Document type: Article Affiliation country: Estados Unidos Country of publication: Alemania