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

G D Te Raa, I A M Derks, V Navrkalova, A Skowronska, P D Moerland, J van Laar, C Oldreive, H Monsuur, M Trbusek, J Malcikova, M Lodén, C H Geisler, J Hüllein, A Jethwa, T Zenz, S Pospisilova, T Stankovic, M H J van Oers, A P Kater, E Eldering

Research output: Contribution to journalArticlepeer-review

50 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1133-42
Number of pages10
Issue number5
Early online date5 Nov 2014
Publication statusPublished - May 2015


  • Apoptosis
  • Ataxia Telangiectasia Mutated Proteins
  • Cohort Studies
  • DNA Damage
  • DNA Mutational Analysis
  • Doxorubicin
  • Flow Cytometry
  • Gene Deletion
  • Gene Expression Regulation, Leukemic
  • Genome, Human
  • Histones
  • Humans
  • Imidazoles
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Mutation
  • Phosphoproteins
  • Piperazines
  • Prognosis
  • Receptor, Notch1
  • Ribonucleoprotein, U2 Small Nuclear
  • Tumor Suppressor Protein p53
  • Vidarabine


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