title: The impact of SF3B1 mutations in CLL on the DNA-damage response.
abstract: 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.
authors.affiliation: 1] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: G D
authors.initials: GD
authors.lastname: Te Raa
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: I A M
authors.initials: IA
authors.lastname: Derks
authors.affiliation: Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: V
authors.initials: V
authors.lastname: Navrkalova
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: A
authors.initials: A
authors.lastname: Skowronska
authors.affiliation: Bioinformatics Laboratory, Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: P D
authors.initials: PD
authors.lastname: Moerland
authors.affiliation: 1] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: van Laar
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: C
authors.initials: C
authors.lastname: Oldreive
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Monsuur
authors.affiliation: Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: M
authors.initials: M
authors.lastname: Trbusek
authors.affiliation: Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: J
authors.initials: J
authors.lastname: Malcikova
authors.affiliation: MRC-Holland, Amsterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Lodén
authors.affiliation: Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
authors.forename: C H
authors.initials: CH
authors.lastname: Geisler
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Hüllein
authors.affiliation: Department of Translational Oncology, National Center for Tumor Diseases (NCT), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Jethwa
authors.affiliation: 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.
authors.forename: T
authors.initials: T
authors.lastname: Zenz
authors.affiliation: Department of Molecular Medicine, Central European Institute of Technology, Masaryk University, Brno, Czech Republic.
authors.forename: S
authors.initials: S
authors.lastname: Pospisilova
authors.affiliation: School of Cancer Sciences, University of Birmingham, Birmingham, UK.
authors.forename: T
authors.initials: T
authors.lastname: Stankovic
authors.affiliation: 1] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.
authors.forename: M H J
authors.initials: MH
authors.lastname: van Oers
authors.affiliation: 1] Department of Hematology, Academic Medical Center, Amsterdam, The Netherlands [2] Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.
authors.forename: A P
authors.initials: AP
authors.lastname: Kater
authors.affiliation: 1] Department of Experimental Immunology, Academic Medical Center, Amsterdam, The Netherlands [2] Lymphoma and Myeloma Center Amsterdam (LYMMCARE), Amsterdam, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Eldering
mesh_terms: D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D015331:Cohort Studies; D004249:DNA Damage; D004252:DNA Mutational Analysis; D004317:Doxorubicin / Q000494:pharmacology; D005434:Flow Cytometry; D017353:Gene Deletion; D015973:Gene Expression Regulation, Leukemic; D015894:Genome, Human; D006657:Histones / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics*; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics*; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1 / Q000235:genetics; D017413:Ribonucleoprotein, U2 Small Nuclear / Q000235:genetics*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: C468783:H2AX protein, human; D006657:Histones; D007093:Imidazoles; C497761:NOTCH1 protein, human; D010750:Phosphoproteins; D010879:Piperazines; D000072260:RNA Splicing Factors; D051881:Receptor, Notch1; D017413:Ribonucleoprotein, U2 Small Nuclear; C112491:SF3B1 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C482205:nutlin 3; D004317:Doxorubicin; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D014740:Vidarabine; C024352:fludarabine