The impact of SF3B1 mutations in CLL on the DNA-damage response.

Autor:	Te Raa GD; 1] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands., Derks IA; Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands., Navrkalova V; Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic., Skowronska A; School of Cancer Sciences, University of Birmingham, Birmingham, UK., Moerland PD; Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands., van Laar J; 1] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands., Oldreive C; School of Cancer Sciences, University of Birmingham, Birmingham, UK., Monsuur H; Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands., Trbusek M; Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic., Malcikova J; Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic., Lodén M; MRC-Holland, Amsterdam, The Netherlands., Geisler CH; Department of Hematology, Rigshospitalet, Copenhagen, Denmark., Hüllein J; Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany., Jethwa A; Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany., Zenz T; 1] Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany [2] Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany., Pospisilova S; Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic., Stankovic T; School of Cancer Sciences, University of Birmingham, Birmingham, UK., van Oers MH; 1] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands., Kater AP; 1] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands., Eldering E; 1] Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands [2] Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.
Jazyk:	angličtina
Zdroj:	Leukemia [Leukemia] 2015 May; Vol. 29 (5), pp. 1133-42. Date of Electronic Publication: 2014 Nov 05.
DOI:	10.1038/leu.2014.318
Abstrakt:	Mutations or deletions in TP53 or ATM are well-known determinants of poor prognosis in chronic lymphocytic leukemia (CLL), but only account for approximately 40% of chemo-resistant patients. Genome-wide sequencing has uncovered novel mutations in the splicing factor sf3b1, that were in part associated with ATM aberrations, suggesting functional synergy. We first performed detailed genetic analyses in a CLL cohort (n=110) containing ATM, SF3B1 and TP53 gene defects. Next, we applied a newly developed multiplex assay for p53/ATM target gene induction and measured apoptotic responses to DNA damage. Interestingly, SF3B1 mutated samples without concurrent ATM and TP53 aberrations (sole SF3B1) displayed partially defective ATM/p53 transcriptional and apoptotic responses to various DNA-damaging regimens. In contrast, NOTCH1 or K/N-RAS mutated CLL displayed normal responses in p53/ATM target gene induction and apoptosis. In sole SF3B1 mutated cases, ATM kinase function remained intact, and γH2AX formation, a marker for DNA damage, was increased at baseline and upon irradiation. Our data demonstrate that single mutations in sf3b1 are associated with increased DNA damage and/or an aberrant response to DNA damage. Together, our observations may offer an explanation for the poor prognosis associated with SF3B1 mutations.
Databáze:	MEDLINE
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