TY - JOUR
T1 - Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia
AU - Papakonstantinou, Nikos
AU - Ntoufa, Stavroula
AU - Tsagiopoulou, Maria
AU - Moysiadis, Theodoros
AU - Bhoi, Sujata
AU - Malousi, Andigoni
AU - Psomopoulos, Fotis
AU - Mansouri, Larry
AU - Laidou, Stamatia
AU - Papazoglou, Despoina
AU - Gounari, Maria
AU - Pasentsis, Konstantinos
AU - Plevova, Karla
AU - Kuci-Emruli, Venera
AU - Duran-Ferrer, Marti
AU - Davis, Zadie
AU - Ek, Sara
AU - Rossi, Davide
AU - Gaidano, Gianluca
AU - Ritgen, Matthias
AU - Oscier, David
AU - Stavroyianni, Niki
AU - Pospisilova, Sarka
AU - Davi, Frederic
AU - Ghia, Paolo
AU - Hadzidimitriou, Anastasia
AU - Belessi, Chrysoula
AU - Martin-Subero, Jose I.
AU - Pott, Christiane
AU - Rosenquist, Richard
AU - Stamatopoulos, Kostas
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
KW - CLL
KW - DNA methylation
KW - gene expression
KW - stereotypy
KW - TP63
U2 - 10.1002/ijc.31999
DO - 10.1002/ijc.31999
M3 - Article
C2 - 30447004
AN - SCOPUS:85060151431
SN - 0020-7136
VL - 144
SP - 2695
EP - 2706
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 11
ER -