Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia

Research output: Contribution to journalArticle

Abstract

Chronic lymphocytic leukemia (CLL) stereotyped subsets #6 and #8 include cases expressing unmutated B cell receptor immunoglobulin (BcR IG) (U-CLL). Subset #6 (IGHV1-69/IGKV3-20) is less aggressive compared to subset #8 (IGHV4-39/IGKV1(D)-39) which has the highest risk for Richter's transformation among all CLL. The underlying reasons for this divergent clinical behavior are not fully elucidated. To gain insight into this issue, here we focused on epigenomic signatures and their links with gene expression, particularly investigating genome-wide DNA methylation profiles in subsets #6 and #8 as well as other U-CLL cases not expressing stereotyped BcR IG. We found that subset #8 showed a distinctive DNA methylation profile compared to all other U-CLL cases, including subset #6. Integrated analysis of DNA methylation and gene expression revealed significant correlation for several genes, particularly highlighting a relevant role for the TP63 gene which was hypomethylated and overexpressed in subset #8. This observation was validated by quantitative PCR, which also revealed TP63 mRNA overexpression in additional nonsubset U-CLL cases. BcR stimulation had distinct effects on p63 protein expression, particularly leading to induction in subset #8, accompanied by increased CLL cell survival. This pro-survival effect was also supported by siRNA-mediated downregulation of p63 expression resulting in increased apoptosis. In conclusion, we report that DNA methylation profiles may vary even among CLL patients with similar somatic hypermutation status, supporting a compartmentalized approach to dissecting CLL biology. Furthermore, we highlight p63 as a novel prosurvival factor in CLL, thus identifying another piece of the complex puzzle of clinical aggressiveness.

Details

Authors
  • Nikos Papakonstantinou
  • Stavroula Ntoufa
  • Maria Tsagiopoulou
  • Theodoros Moysiadis
  • Sujata Bhoi
  • Andigoni Malousi
  • Fotis Psomopoulos
  • Larry Mansouri
  • Stamatia Laidou
  • Despoina Papazoglou
  • Maria Gounari
  • Konstantinos Pasentsis
  • Karla Plevova
  • Marti Duran-Ferrer
  • Zadie Davis
  • Davide Rossi
  • Gianluca Gaidano
  • Matthias Ritgen
  • David Oscier
  • Niki Stavroyianni
  • Sarka Pospisilova
  • Frederic Davi
  • Paolo Ghia
  • Anastasia Hadzidimitriou
  • Chrysoula Belessi
  • Jose I. Martin-Subero
  • Christiane Pott
  • Richard Rosenquist
  • Kostas Stamatopoulos
Organisations
External organisations
  • Center for Research and Technology Hellas
  • Uppsala University
  • Aristotle University of Thessaloniki
  • Karolinska Institutet
  • University Hospital Brno
  • University of Barcelona
  • Royal Bournemouth Hospital
  • University of Eastern Piedmont
  • University Medical Center Schleswig-Holstein Campus Kiel
  • George Papanicolaou General Hospital
  • Vita-Salute San Raffaele University
  • Oncology Institute of Southern Switzerland
  • Pierre and Marie Curie University
  • Nikea General Hospital, Piraeus
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics

Keywords

  • CLL, DNA methylation, gene expression, stereotypy, TP63
Original languageEnglish
Pages (from-to)2695-2706
JournalInternational Journal of Cancer
Volume144
Issue number11
Early online date2019
Publication statusPublished - 2019
Publication categoryResearch
Peer-reviewedYes