Frontiers in Oncology (Jan 2021)
The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer
- Alexander C. Leeksma,
- Alexander C. Leeksma,
- Alexander C. Leeksma,
- Ingrid A. M. Derks,
- Ingrid A. M. Derks,
- M. Haidar Kasem,
- Emine Kilic,
- Annelies de Klein,
- Martine J. Jager,
- Arjan A. van de Loosdrecht,
- Joop H. Jansen,
- Veronika Navrkalova,
- Laura M. Faber,
- Nadja Zaborsky,
- Nadja Zaborsky,
- Nadja Zaborsky,
- Alexander Egle,
- Alexander Egle,
- Alexander Egle,
- Thorsten Zenz,
- Sarka Pospisilova,
- Omar Abdel-Wahab,
- Arnon P. Kater,
- Arnon P. Kater,
- Eric Eldering,
- Eric Eldering
Affiliations
- Alexander C. Leeksma
- Department of Hematology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands
- Alexander C. Leeksma
- Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands
- Alexander C. Leeksma
- Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) and Amsterdam Infection and Immunity Institute (AIII), Amsterdam, Netherlands
- Ingrid A. M. Derks
- Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands
- Ingrid A. M. Derks
- Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) and Amsterdam Infection and Immunity Institute (AIII), Amsterdam, Netherlands
- M. Haidar Kasem
- Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany
- Emine Kilic
- Department of Ophthalmology and Clinical Genetics Erasmus MC, Rotterdam, Netherlands
- Annelies de Klein
- Department of Ophthalmology and Clinical Genetics Erasmus MC, Rotterdam, Netherlands
- Martine J. Jager
- Department of Ophthalmology, LUMC, Leiden, Netherlands
- Arjan A. van de Loosdrecht
- Department of Hematology, Amsterdam University Medical Centers, Location VUMC, Amsterdam, Netherlands
- Joop H. Jansen
- Laboratory of Hematology, Department Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands
- Veronika Navrkalova
- Center of Molecular Biology and Gene Therapy, Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Center of Molecular Medicine, CEITEC, Masaryk University, Brno, Czechia
- Laura M. Faber
- 0Department of Internal Medicine, Rode Kruis Ziekenhuis, Beverwijk, Netherlands
- Nadja Zaborsky
- 1Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
- Nadja Zaborsky
- 2Department of Internal Medicine III with Haematology, Salzburg Cancer Research Institute—Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg, Austria
- Nadja Zaborsky
- 3Department of Internal Medicine III with Haematology, Cancer Cluster Salzburg, Salzburg, Austria
- Alexander Egle
- 1Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria
- Alexander Egle
- 2Department of Internal Medicine III with Haematology, Salzburg Cancer Research Institute—Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg, Austria
- Alexander Egle
- 3Department of Internal Medicine III with Haematology, Cancer Cluster Salzburg, Salzburg, Austria
- Thorsten Zenz
- 4Department of Oncology and Haematology, University Hospital and University of Zurich, Zurich, Switzerland
- Sarka Pospisilova
- Center of Molecular Biology and Gene Therapy, Department of Internal Medicine-Hematology and Oncology, University Hospital Brno and Center of Molecular Medicine, CEITEC, Masaryk University, Brno, Czechia
- Omar Abdel-Wahab
- 5Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States
- Arnon P. Kater
- Department of Hematology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands
- Arnon P. Kater
- Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands
- Eric Eldering
- Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands
- Eric Eldering
- Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) and Amsterdam Infection and Immunity Institute (AIII), Amsterdam, Netherlands
- DOI
- https://doi.org/10.3389/fonc.2020.609409
- Journal volume & issue
-
Vol. 10
Abstract
Recurrent mutations in splicing factor 3B subunit 1 (SF3B1) have been identified in several malignancies and are associated with an increased expression of 3’ cryptic transcripts as a result of alternative branchpoint recognition. A large fraction of cryptic transcripts associated with SF3B1 mutations is expected to be sensitive for RNA degradation via nonsense-mediated mRNA decay (NMD). Several studies indicated alterations in various signaling pathways in SF3B1-mutated cells, including an impaired DNA damage response (DDR) in chronic lymphocytic leukemia (CLL). In this study, we investigated isogenic cell lines and treatment naïve primary CLL samples without any TP53 and/or ATM defect, and found no significant effects of SF3B1 mutations on the ATM/p53 response, phosphorylation of H2AX and sensitivity to fludarabine. Cryptic transcripts associated with SF3B1 mutation status were observed at relatively low levels compared to the canonical transcripts and were validated as target for mRNA degradation via NMD. Expression of cryptic transcripts increased after NMD inhibition. In conclusion, our results confirm involvement of NMD in the biological effects of SF3B1 mutations. Further studies may elucidate whether SF3B1-mutant patients could benefit from NMD modulatory agents.
Keywords
