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

Research output: Contribution to journalArticle

Authors

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

Colleges, School and Institutes

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.

Details

Original languageEnglish
Pages (from-to)1133-42
Number of pages10
JournalLeukemia
Volume29
Issue number5
Publication statusPublished - May 2015

Keywords

  • 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