Whole-exome sequencing in relapsing chronic lymphocytic leukemia: clinical impact of recurrent RPS15 mutations.

Research output: Contribution to journalArticle

Abstract

Fludarabine, cyclophosphamide and rituximab (FCR) is first-line treatment for medically fit chronic lymphocytic leukemia (CLL) patients, however despite good response rates many patients eventually relapse. Whilst recent high-throughput studies have identified novel recurrent genetic lesions in adverse-prognostic CLL, the mechanisms leading to relapse after FCR therapy are not completely understood. To gain insight into this issue, we performed whole-exome sequencing of sequential samples from 41 CLL patients who were uniformly treated with FCR but relapsed after a median of 2 years. In addition to mutations with known adverse-prognostic impact (TP53, NOTCH1, ATM, SF3B1, NFKBIE, BIRC3) a large proportion of cases (19.5%) harbored mutations in RPS15, a gene encoding a component of the 40S ribosomal subunit. Extended screening, totaling 1119 patients, supported a role for RPS15 mutations in aggressive CLL, with one-third of RPS15-mutant cases also carrying TP53 aberrations. In most cases selection of dominant, relapse-specific subclones was observed over time. However, RPS15 mutations were clonal prior to treatment and remained stable at relapse. Notably, all RPS15 mutations represented somatic missense variants and resided within a 7 amino-acid evolutionarily conserved region. We confirmed the recently postulated direct interaction between RPS15 and MDM2/MDMX and transient expression of mutant RPS15 revealed defective regulation of endogenous p53 compared to wildtype RPS15. In summary, we provide novel insights into the heterogeneous genetic landscape of CLL relapsing after FCR treatment and highlight a novel mechanism underlying clinical aggressiveness involving a mutated ribosomal protein, potentially representing an early genetic lesion in CLL pathobiology.

Details

Authors
  • Viktor Ljungström
  • Diego Cortese
  • Emma Young
  • Tatjana Pandzic
  • Larry Mansouri
  • Karla Plevova
  • Stavroula Ntoufa
  • Panagiotis Baliakas
  • Ruth Clifford
  • Lesley-Ann Sutton
  • Stuart Blakemore
  • Niki Stavroyianni
  • Andreas Agathangelidis
  • Davide Rossi
  • Martin Höglund
  • Jana Kotaskova
  • Chrysoula Belessi
  • Nicholas Chiorazzi
  • Panagiotis Panagiotidis
  • Anton W Langerak
  • Karin E Smedby
  • David Oscier
  • Gianluca Gaidano
  • Anna Schuh
  • Frederic Davi
  • Christiane Pott
  • Jonathan C Strefford
  • Livio Trentin
  • Sarka Pospisilova
  • Paolo Ghia
  • Kostas Stamatopoulos
  • Tobias Sjöblom
  • Richard Rosenquist
Organisations
External organisations
  • Uppsala University
  • Masaryk University
  • Center for Research and Technology Hellas
  • University of Oxford
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Hematology
Original languageEnglish
JournalBlood
Volume127
Issue number8
Early online date2015 Dec 16
Publication statusPublished - 2016
Publication categoryResearch
Peer-reviewedYes