The impact of SF3B1 mutations in CLL on the DNA-damage response
| Autor: | Jitka Malčíková, G.D. te Raa, E. Eldering, Hanneke N. Monsuur, Arnon P. Kater, Alexander Jethwa, Tatjana Stankovic, Ingrid A. M. Derks, Veronika Navrkalová, Šárka Pospíšilová, M. Lodén, Ceri E. Oldreive, Perry D. Moerland, Anna Skowronska, M. H. J. Van Oers, Thorsten Zenz, J van Laar, Martin Trbušek, Christian H. Geisler, Jennifer Hüllein |
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| Přispěvatelé: | Other departments, AII - Amsterdam institute for Infection and Immunity, Experimental Immunology, APH - Amsterdam Public Health, Epidemiology and Data Science, CCA -Cancer Center Amsterdam, Clinical Haematology |
| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Cancer Research
DNA damage Chronic lymphocytic leukemia DNA Mutational Analysis Apoptosis Ataxia Telangiectasia Mutated Proteins Biology medicine.disease_cause Piperazines Cohort Studies Histones 03 medical and health sciences Splicing factor 0302 clinical medicine medicine Humans Receptor Notch1 Gene 030304 developmental biology 0303 health sciences Mutation Gene Expression Regulation Leukemic Genome Human Imidazoles Hematology Ribonucleoprotein U2 Small Nuclear Flow Cytometry Phosphoproteins Prognosis medicine.disease Leukemia Lymphocytic Chronic B-Cell Molecular biology 3. Good health Histone Oncology Doxorubicin 030220 oncology & carcinogenesis Cancer research biology.protein Human genome RNA Splicing Factors Tumor Suppressor Protein p53 Gene Deletion Vidarabine DNA Damage |
| Zdroj: | Leukemia, 29(5), 1133-1142. Nature Publishing Group Leukemia |
| ISSN: | 0887-6924 |
| Popis: | 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: | OpenAIRE |
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