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

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

Papakonstantinou, Nikos (författare): Uppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab,Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece,Center for Research and Technology Hellas

Ntoufa, Stavroula (författare): Uppsala University,Uppsala universitet,Institutionen för immunologi, genetik och patologi,Science for Life Laboratory, SciLifeLab,Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece,Center for Research and Technology Hellas

Tsagiopoulou, Maria (författare): Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece,Center for Research and Technology Hellas

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Moysiadis, Theodoros (författare): Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece,Center for Research and Technology Hellas

Bhoi, Sujata (författare): Uppsala University,Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab

Malousi, Andigoni (författare): Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece;Aristotle Univ Thessaloniki, Med Sch, Lab Biol Chem, Thessaloniki, Greece,Aristotle University of Thessaloniki,Center for Research and Technology Hellas

Psomopoulos, Fotis (författare): Karolinska Institute,Karolinska Institutet,Center for Research and Technology Hellas

Mansouri, Larry (författare): Uppsala University,Karolinska Institute,Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi,Karolinska Institutet, Dept Mol Med & Surg, Stockholm, Sweden

Laidou, Stamatia (författare): Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece,Center for Research and Technology Hellas

Papazoglou, Despoina (författare): Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece,Center for Research and Technology Hellas

Gounari, Maria (författare): Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece,Center for Research and Technology Hellas

Pasentsis, Konstantinos (författare): Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece,Center for Research and Technology Hellas

Plevova, Karla (författare): Univ Hosp Brno, Ctr Mol Biol & Gene Therapy, Dept Internal Med Hematol & Oncol, Brno, Czech Republic;Masaryk Univ, Med Fac, Brno, Czech Republic,University Hospital Brno

Kuci-Emruli, Venera (författare): Lund University,Lunds universitet,Institutionen för immunteknologi,Institutioner vid LTH,Lunds Tekniska Högskola,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH

Duran-Ferrer, Marti (författare): Univ Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Dept Fundamentos Clin, Barcelona, Spain,University of Barcelona

Davis, Zadie (författare): Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England,Royal Bournemouth Hospital

Ek, Sara (författare): Lund University,Lunds universitet,Institutionen för immunteknologi,Institutioner vid LTH,Lunds Tekniska Högskola,Department of Immunotechnology,Departments at LTH,Faculty of Engineering, LTH

Rossi, Davide (författare): Oncol Inst Southern Switzerland, Hematol, Bellinzona, Switzerland;Inst Oncol Res, Bellinzona, Switzerland,Oncology Institute of Southern Switzerland

Gaidano, Gianluca (författare): Amedeo Avogadro Univ Eastern Piedmt, Dept Translat Med, Div Hematol, Novara, Italy,University of Eastern Piedmont

Ritgen, Matthias (författare): Univ Hosp Schleswig Holstein, Med Dept 2, Kiel, Germany,University Medical Center Schleswig-Holstein

Oscier, David (författare): Royal Bournemouth Hosp, Dept Haematol, Bournemouth, Dorset, England,Royal Bournemouth Hospital

Stavroyianni, Niki (författare): G Papanicolaou Hosp, Hematol Dept, Thessaloniki, Greece;G Papanicolaou Hosp, HCT Unit, Thessaloniki, Greece,George Papanicolaou General Hospital

Pospisilova, Sarka (författare): Univ Hosp Brno, Ctr Mol Biol & Gene Therapy, Dept Internal Med Hematol & Oncol, Brno, Czech Republic;Masaryk Univ, Med Fac, Brno, Czech Republic,University Hospital Brno

Davi, Frederic (författare): Hematol Dept, Paris, France;Univ Paris 06, Paris, France,Paris-Sorbonne University

Ghia, Paolo (författare): IRCCS San Raffaele Sci Inst, Dept Oncohematol, Div Expt Oncol, Milan, Italy;Univ Vita Salute San Raffaele, Milan, Italy,Vita-Salute San Raffaele University

Hadzidimitriou, Anastasia (författare): Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece,Center for Research and Technology Hellas

Belessi, Chrysoula (författare): Nikea Gen Hosp, Hematol Dept, Athens, Greece,Nikea General Hospital, Piraeus

Martin-Subero, Jose, I (författare): Univ Barcelona, Inst Invest Biomed August Pi & Sunyer IDIBAPS, Dept Fundamentos Clin, Barcelona, Spain,University of Barcelona

Pott, Christiane (författare): Univ Hosp Schleswig Holstein, Med Dept 2, Kiel, Germany,University Medical Center Schleswig-Holstein

Rosenquist, Richard (författare): Uppsala University,Karolinska Institute,Uppsala universitet,Science for Life Laboratory, SciLifeLab,Experimentell och klinisk onkologi,Karolinska Institutet, Dept Mol Med & Surg, Stockholm, Sweden

Stamatopoulos, Kostas (författare): Uppsala University,Uppsala universitet,Experimentell och klinisk onkologi,Science for Life Laboratory, SciLifeLab,Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece,Center for Research and Technology Hellas

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2019-01-15
2019
Engelska.
Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 144:11, s. 2695-2706

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Tidskriftsartikel (refereegranskat)

Abstract Ämnesord

Stäng

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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)

Nyckelord

CLL
stereotypy
DNA methylation
gene expression
TP63
CLL
DNA methylation
gene expression
stereotypy
TP63

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