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

J 2019

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

PAPAKONSTANTINOU, N.; S. NTOUFA; M. TSAGIOPOULOU; T. MOYSIADIS; S. BHOI et al.

Základní údaje

Originální název

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

Autoři

Vydání

International journal of cancer, HOBOKEN, International Union Against Cancer, 2019, 0020-7136

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

30204 Oncology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

URL

Impakt faktor

Impact factor: 5.145

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14110/19:00108479

Organizační jednotka

Lékařská fakulta

Klíčová slova anglicky

CLL; stereotypy; DNA methylation; gene expression; TP63

Štítky

14110212, rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 15. 7. 2019 13:08, Soňa Böhmová

Anotace

V originále

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. What's new? In chronic lymphocytic leukemia (CLL), cases with unmutated immunoglobulin receptors (U-CLL) are generally associated with inferior outcome, albeit still displaying considerable heterogeneity. Might such differences in CLL progression be explained by epigenetics? In this study, the authors found that an unusually aggressive subset of CLLs called subset #8 has a distinctive DNA-methylation profile. They also found that p63 is a novel pro-survival factor for CLL cells. These molecular studies may lead to new prognostic biomarkers, and possibly new therapeutic targets, for CLL.

Návaznosti

LQ1601, projekt VaV

Název: CEITEC 2020 (Akronym: CEITEC2020)

Investor: Ministerstvo školství, mládeže a tělovýchovy ČR, CEITEC 2020

NV15-30015A, projekt VaV

Název: Analýza klonální heterogenity chronické lymfocytární leukemie pomoci sekvenování nové generace genu pro B-buněčný receptor. Národní studie.

692298, interní kód MU

Název: MEDGENET - Medical genomics and epigenomics network (Akronym: MEDGENET)

Investor: Evropská unie, MEDGENET - Medical genomics and epigenomics network, Spreading excellence and widening participation

Přiložené soubory

Papakonstantinou_et_al_Supplementary_Figures_IJC_Final_Accepted.doc Verze souboru

Papakonstantinou_et_al_main_document.docx Verze souboru

Papakonstantinou_et_al_Supplementary_Tables_IJC_2nd_Revision.xlsx Verze souboru

Table_1_Final_Accepted.doc Verze souboru

Citovat

PAPAKONSTANTINOU, N.; S. NTOUFA; M. TSAGIOPOULOU; T. MOYSIADIS; S. BHOI; A. MALOUSI; F. PSOMOPOULOS; L. MANSOURI; S. LAIDOU; D. PAPAZOGLOU; M. GOUNARI; K. PASENTSIS; Karla PLEVOVÁ; V. KUCI-EMRULI; M. DURAN-FERRER; Z. DAVIS; S. EK; D. ROSSI; G. GAIDANO; M. RITGEN; D. OSCIER; N. STAVROYIANNI; Šárka POSPÍŠILOVÁ; F. DAVI; P. GHIA; A. HADZIDIMITRIOU; C. BELESSI; J.I. MARTIN-SUBERO; C. POTT; R. ROSENQUIST a K. STAMATOPOULOS. Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia. International journal of cancer. HOBOKEN: International Union Against Cancer, 2019, roč. 144, č. 11, s. 2695-2706. ISSN 0020-7136. Dostupné z: https://doi.org/10.1002/ijc.31999.

@article{1534298,
   author = {Papakonstantinou, N. and Ntoufa, S. and Tsagiopoulou, M. and Moysiadis, T. and Bhoi, S. and Malousi, A. and Psomopoulos, F. and Mansouri, L. and Laidou, S. and Papazoglou, D. and Gounari, M. and Pasentsis, K. and Plevová, Karla and KuciandEmruli, V. and DuranandFerrer, M. and Davis, Z. and Ek, S. and Rossi, D. and Gaidano, G. and Ritgen, M. and Oscier, D. and Stavroyianni, N. and Pospíšilová, Šárka and Davi, F. and Ghia, P. and Hadzidimitriou, A. and Belessi, C. and MartinandSubero, J.I. and Pott, C. and Rosenquist, R. and Stamatopoulos, K.},
   article_location = {HOBOKEN},
   article_number = {11},
   doi = {https://doi.org/10.1002/ijc.31999},
   keywords = {CLL; stereotypy; DNA methylation; gene expression; TP63},
   language = {eng},
   issn = {0020-7136},
   journal = {International journal of cancer},
   title = {Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia},
   url = {http://dx.doi.org/10.1002/ijc.31999},
   volume = {144},
   year = {2019}
}

TY  - JOUR
ID  - 1534298
AU  - Papakonstantinou, N. - Ntoufa, S. - Tsagiopoulou, M. - Moysiadis, T. - Bhoi, S. - Malousi, A. - Psomopoulos, F. - Mansouri, L. - Laidou, S. - Papazoglou, D. - Gounari, M. - Pasentsis, K. - Plevová, Karla - Kuci-Emruli, V. - Duran-Ferrer, M. - Davis, Z. - Ek, S. - Rossi, D. - Gaidano, G. - Ritgen, M. - Oscier, D. - Stavroyianni, N. - Pospíšilová, Šárka - Davi, F. - Ghia, P. - Hadzidimitriou, A. - Belessi, C. - Martin-Subero, J.I. - Pott, C. - Rosenquist, R. - Stamatopoulos, K.
PY  - 2019
TI  - Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia
JF  - International journal of cancer
VL  - 144
IS  - 11
SP  - 2695-2706
EP  - 2695-2706
PB  - International Union Against Cancer
SN  - 00207136
KW  - CLL
KW  - stereotypy
KW  - DNA methylation
KW  - gene expression
KW  - TP63
UR  - http://dx.doi.org/10.1002/ijc.31999
L2  - http://dx.doi.org/10.1002/ijc.31999
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. What's new? In chronic lymphocytic leukemia (CLL), cases with unmutated immunoglobulin receptors (U-CLL) are generally associated with inferior outcome, albeit still displaying considerable heterogeneity. Might such differences in CLL progression be explained by epigenetics? In this study, the authors found that an unusually aggressive subset of CLLs called subset #8 has a distinctive DNA-methylation profile. They also found that p63 is a novel pro-survival factor for CLL cells. These molecular studies may lead to new prognostic biomarkers, and possibly new therapeutic targets, for CLL.
ER  -

PAPAKONSTANTINOU, N.; S. NTOUFA; M. TSAGIOPOULOU; T. MOYSIADIS; S. BHOI; A. MALOUSI; F. PSOMOPOULOS; L. MANSOURI; S. LAIDOU; D. PAPAZOGLOU; M. GOUNARI; K. PASENTSIS; Karla PLEVOVÁ; V. KUCI-EMRULI; M. DURAN-FERRER; Z. DAVIS; S. EK; D. ROSSI; G. GAIDANO; M. RITGEN; D. OSCIER; N. STAVROYIANNI; Šárka POSPÍŠILOVÁ; F. DAVI; P. GHIA; A. HADZIDIMITRIOU; C. BELESSI; J.I. MARTIN-SUBERO; C. POTT; R. ROSENQUIST a K. STAMATOPOULOS. Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia. \textit{International journal of cancer}. HOBOKEN: International Union Against Cancer, 2019, roč.~144, č.~11, s.~2695-2706. ISSN~0020-7136. Dostupné z: https://doi.org/10.1002/ijc.31999.

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