EGR2 mutations define a new clinically aggressive subgroup of chronic lymphocytic leukemia


  • E. Young
  • D. Noerenberg
  • L. Mansouri
  • V. Ljungström
  • M. Frick
  • L.A. Sutton
  • S.J. Blakemore
  • J. Galan-Sousa
  • K. Plevova
  • P. Baliakas
  • D. Rossi
  • R. Clifford
  • D. Roos-Weil
  • V. Navrkalova
  • B. Dörken
  • C.A. Schmitt
  • K.E. Smedby
  • G. Juliusson
  • B. Giacopelli
  • J.S. Blachly
  • C. Belessi
  • P. Panagiotidis
  • N. Chiorazzi
  • F. Davi
  • A.W. Langerak
  • D. Oscier
  • A. Schuh
  • G. Gaidano
  • P. Ghia
  • W. Xu
  • L. Fan
  • O.A. Bernard
  • F. Nguyen-Khac
  • L. Rassenti
  • J. Li
  • T.J. Kipps
  • K. Stamatopoulos
  • S. Pospisilova
  • T. Zenz
  • C.C. Oakes
  • J.C. Strefford
  • R. Rosenquist
  • F. Damm


  • Leukemia


  • Leukemia 31 (7): 1547-1554


  • Recurrent mutations within EGR2 were recently reported in advanced-stage chronic lymphocytic leukemia (CLL) patients and associated with a worse outcome. To study their prognostic impact, 2403 CLL patients were examined for mutations in the EGR2 hotspot region including a screening (n=1283) and two validation cohorts (UK CLL4 trial patients, n=366; CLL Research Consortium (CRC) patients, n=490). Targeted deep-sequencing of 27 known/postulated CLL driver genes was also performed in 38 EGR2-mutated patients to assess concurrent mutations. EGR2 mutations were detected in 91/2403 (3.8%) investigated cases, and associated with younger age at diagnosis, advanced clinical stage, high CD38 expression and unmutated IGHV genes. EGR2-mutated patients frequently carried ATM lesions (42%), TP53 aberrations (18%), and NOTCH1/FBXW7 mutations (16%). EGR2 mutations independently predicted shorter time-to-first-treatment (TTFT) and overall survival (OS) in the screening cohort; they were confirmed associated with reduced TTFT and OS in the CRC cohort and independently predicted short OS from randomization in the UK CLL4 cohort. A particularly dismal outcome was observed among EGR2-mutated patients who also carried TP53 aberrations. In summary, EGR2 mutations were independently associated with an unfavorable prognosis, comparable to CLL patients carrying TP53 aberrations, suggesting that EGR2-mutated patients represent a new patient subgroup with very poor outcome.