JavaScript is NOT enabled !

Please enable JavaScript.

Article

PubMed

This record comes from PubMed

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

Te Raa, G D
Author Te Raa, G D ] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
Derks, I A M
Author Derks, I A M Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
Navrkalova, V
Author Navrkalova, V Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic
Skowronska, A
Author Skowronska, A School of Cancer Sciences, University of Birmingham, Birmingham, UK
Moerland, P D
Author Moerland, P D Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands
van Laar, J
Author van Laar, J ] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
Oldreive, C
Author Oldreive, C School of Cancer Sciences, University of Birmingham, Birmingham, UK
Monsuur, H
Author Monsuur, H Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands
Trbusek, M
Author Trbusek, M Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic
Malcikova, J
Author Malcikova, J Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic
Lodén, M
Author Lodén, M MRC-Holland, Amsterdam, The Netherlands
Geisler, C H
Author Geisler, C H Department of Hematology, Rigshospitalet, Copenhagen, Denmark
Hüllein, J
Author Hüllein, J Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany
Jethwa, A
Author Jethwa, A Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany
Zenz, T
Author Zenz, T ] 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
Author Pospisilova, S Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic
Stankovic, T
Author Stankovic, T School of Cancer Sciences, University of Birmingham, Birmingham, UK
van Oers, M H J
Author van Oers, M H J ] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands
Kater, A P
Author Kater, A P ] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands
Eldering, E
Author Eldering, E ] Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands [2] Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands

Leukemia. 2015 May ; 29 (5) : 1133-42. [epub] 20141105

ISSN 1476-5551 | 0887-6924
Source

Language English Country England, Great Britain Media print-electronic

Document type Journal Article, Research Support, Non-U.S. Gov't

Persistent link https://www.medvik.cz/link/pmid25371178

PubMed 25371178
DOI 10.1038/leu.2014.318
PII: leu2014318
Knihovny.cz E-resources

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.

] Department of Experimental Immunology Academic Medical Center Amsterdam The Netherlands [2] Lymphoma and Myeloma Center Amsterdam Amsterdam The Netherlands

] Department of Hematology Academic Medical Center Amsterdam The Netherlands [2] Department of Experimental Immunology Academic Medical Center Amsterdam The Netherlands

] Department of Hematology Academic Medical Center Amsterdam The Netherlands [2] Lymphoma and Myeloma Center Amsterdam Amsterdam The Netherlands

] Department of Translational Oncology National Center for Tumor Diseases Heidelberg Germany [2] Department of Medicine 5 University Hospital Heidelberg Heidelberg Germany

Bioinformatics Laboratory Department of Clinical Epidemiology Biostatistics and Bioinformatics Academic Medical Center Amsterdam The Netherlands

Department of Experimental Immunology Academic Medical Center Amsterdam The Netherlands

Department of Hematology Rigshospitalet Copenhagen Denmark

Department of Molecular Medicine Central European Institute of Technology Masaryk University Brno Czech Republic

Department of Translational Oncology National Center for Tumor Diseases Heidelberg Germany

MRC Holland Amsterdam The Netherlands

School of Cancer Sciences University of Birmingham Birmingham UK

See more in PubMed