Chronic lymphocytic leukemia with mutated IGHV4-34 receptors: Shared and distinct immunogenetic features and clinical outcomes

Research output: Contribution to journalArticle


Purpose: We sought to investigate whether B cell receptor immunoglobulin (BcR IG) stereotypy is associated with particular clinicobiological features among chronic lymphocytic leukemia (CLL) patients expressing mutated BcR IG (M-CLL) encoded by the IGHV4-34 gene, and also ascertain whether these associations could refine prognostication. Experimental Design: In a series of 19,907 CLL cases with available immunogenetic information, we identified 339 IGHV4-34-expressing cases assigned to one of the four largest stereotyped M-CLL subsets, namely subsets #4, #16, #29 and #201, and investigated in detail their clinicobiological characteristics and disease outcomes. Results: We identified shared and subset-specific patterns of somatic hypermutation (SHM) among patients assigned to these subsets. The greatest similarity was observed between subsets #4 and #16, both including IgG-switched cases (IgG-CLL). In contrast, the least similarity was detected between subsets #16 and #201, the latter concerning IgM/D-expressing CLL. Significant differences between subsets also involved disease stage at diagnosis and the presence of specific genomic aberrations. IgG subsets #4 and #16 emerged as particularly indolent with a significantly (P < 0.05) longer time-to-first-treatment (TTFT; median TTFT: not yet reached) compared with the IgM/D subsets #29 and #201 (median TTFT: 11 and 12 years, respectively). Conclusions: Our findings support the notion that BcR IG stereotypy further refines prognostication in CLL, superseding the immunogenetic distinction based solely on SHM load. In addition, the observed distinct genetic aberration landscapes and clinical heterogeneity suggest that not all M-CLL cases are equal, prompting further research into the underlying biological background with the ultimate aim of tailored patient management.


  • Aliki Xochelli
  • Panagiotis Baliakas
  • Ioannis Kavakiotis
  • Andreas Agathangelidis
  • Lesley-Ann Sutton
  • Eva Minga
  • Stavroula Ntoufa
  • Eugen Tausch
  • Xiao-Jie Yan
  • Tait Shanafelt
  • Karla Plevova
  • Myriam Boudjogra
  • Davide Rossi
  • Zadie Davis
  • Alba Navarro
  • Yorick Sandberg
  • Fie Juhl Vojdeman
  • Lydia Scarfo
  • Niki Stavroyianni
  • Andrey Sudarikov
  • Silvio Veronese
  • Tatiana Tzenou
  • Teodora Karan-Djurasevic
  • Mark Catherwood
  • Dirk Kienle
  • Maria Chatzouli
  • Monica Facco
  • Jasmin Bahlo
  • Christiane Pott
  • Lone Bredo Pedersen
  • Larry Mansouri
  • Karin E. Smedby
  • Charles C Chu
  • Veronique Giudicelli
  • Marie-Paule Lefranc
  • Panagiotis Panagiotidis
  • Achilles Anagnostopoulos
  • Ioannis Vlahavas
  • Darko Antic
  • Livio Trentin
  • Marco Montillo
  • Carsten Niemann
  • Hartmut Dohner
  • Anton W Langerak
  • Sarka Pospisilova
  • Michael Hallek
  • Elias Campo
  • Nicholas Chiorazzi
  • Nikos Maglaveras
  • David Oscier
  • Gianluca Gaidano
  • Diane F. Jelinek
  • Stephan Stilgenbauer
  • Ioanna Chouvarda
  • Nikos Darzentas
  • Chrysoula Belessi
  • Frederic Davi
  • Anastasia Hadzidimitriou
  • Richard Rosenquist
  • Paolo Ghia
  • Kostas Stamatopoulos
External organisations
  • Center for Research and Technology Hellas
  • Uppsala University
  • Aristotle University of Thessaloniki
  • San Raffaele Scientific Institute
  • Karolinska Institutet
  • University of Ulm
  • Feinstein Institute for Medical Research
  • Mayo Clinic Minnesota
  • Masaryk University
  • Pierre and Marie Curie University
  • University of Eastern Piedmont
  • Royal Bournemouth Hospital
  • University of Barcelona
  • Erasmus University Medical Center
  • Copenhagen University Hospital
  • George Papanicolaou General Hospital
  • National Research Center for Hematology
  • Niguarda Hospital
  • National and Kapodistrian University of Athens
  • University of Belgrade
  • Belfast City Hospital
  • Nikea General Hospital, Piraeus
  • University of Padova
  • University Hospital of Cologne
  • University Medical Center Schleswig-Holstein Campus Kiel
  • Institut de Génétique Humaine
  • Skåne University Hospital
  • Vita-Salute San Raffaele University
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cancer and Oncology


  • LEUKEMIA, IGHV4-34 Receptors, Clinical Outcomes
Original languageEnglish
Pages (from-to)5292-5301
Number of pages10
JournalClinical Cancer Research
Issue number17
Publication statusPublished - 2017 Sep 1
Publication categoryResearch