The Effect of SF3B1 Mutation on the DNA Damage Response and Nonsense-Mediated mRNA Decay in Cancer.

Autor:	Leeksma AC; Department of Hematology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands.; Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) and Amsterdam Infection and Immunity Institute (AIII), Amsterdam, Netherlands., Derks IAM; Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) and Amsterdam Infection and Immunity Institute (AIII), Amsterdam, Netherlands., Kasem MH; Translational Functional Cancer Genomics, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany., Kilic E; Department of Ophthalmology and Clinical Genetics Erasmus MC, Rotterdam, Netherlands., de Klein A; Department of Ophthalmology and Clinical Genetics Erasmus MC, Rotterdam, Netherlands., Jager MJ; Department of Ophthalmology, LUMC, Leiden, Netherlands., van de Loosdrecht AA; Department of Hematology, Amsterdam University Medical Centers, Location VUMC, Amsterdam, Netherlands., Jansen JH; Laboratory of Hematology, Department Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands., Navrkalova V; 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., Faber LM; Department of Internal Medicine, Rode Kruis Ziekenhuis, Beverwijk, Netherlands., Zaborsky N; Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.; Department of Internal Medicine III with Haematology, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg, Austria.; Department of Internal Medicine III with Haematology, Cancer Cluster Salzburg, Salzburg, Austria., Egle A; Department of Internal Medicine III with Haematology, Medical Oncology, Haemostaseology, Infectiology and Rheumatology, Oncologic Center, Paracelsus Medical University, Salzburg, Austria.; Department of Internal Medicine III with Haematology, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Salzburg, Austria.; Department of Internal Medicine III with Haematology, Cancer Cluster Salzburg, Salzburg, Austria., Zenz T; Department of Oncology and Haematology, University Hospital and University of Zurich, Zurich, Switzerland., Pospisilova S; 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., Abdel-Wahab O; Human Oncology and Pathogenesis Program and Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United States., Kater AP; Department of Hematology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands.; Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands., Eldering E; Department of Experimental Immunology, Amsterdam University Medical Centers, Location AMC, University of Amsterdam, Amsterdam, Netherlands.; Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Cancer Center Amsterdam (CCA) and Amsterdam Infection and Immunity Institute (AIII), Amsterdam, Netherlands.
Jazyk:	angličtina
Zdroj:	Frontiers in oncology [Front Oncol] 2021 Jan 29; Vol. 10, pp. 609409. Date of Electronic Publication: 2021 Jan 29 (Print Publication: 2020).
DOI:	10.3389/fonc.2020.609409
Abstrakt:	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. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Leeksma, Derks, Kasem, Kilic, de Klein, Jager, van de Loosdrecht, Jansen, Navrkalova, Faber, Zaborsky, Egle, Zenz, Pospisilova, Abdel-Wahab, Kater and Eldering.)
Databáze:	MEDLINE
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