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Integrated epigenomic and transcriptomic analysis reveals TP63 as a novel player in clinically aggressive chronic lymphocytic leukemia
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece.
Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece.
Ctr Res & Technol Hellas, Inst Appl Biosci, 6th Km Charilaou Thermi Rd, GR-57001 Thessaloniki, Greece.
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2019 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 144, no 11, p. 2695-2706Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 144, no 11, p. 2695-2706
Keywords [en]
CLL, stereotypy, DNA methylation, gene expression, TP63
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-384059DOI: 10.1002/ijc.31999ISI: 000467099500009PubMedID: 30447004OAI: oai:DiVA.org:uu-384059DiVA, id: diva2:1328216
Funder
EU, Horizon 2020, 644906Swedish Cancer SocietyKnut and Alice Wallenberg FoundationEU, Horizon 2020, 692298Swedish Research CouncilEU, Horizon 2020, 702714
Note

De 3 första författarna delar förstaförfattarskapet.

Available from: 2019-06-20 Created: 2019-06-20 Last updated: 2019-06-20Bibliographically approved

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Bhoi, SujataMansouri, LarryRosenquist, RichardStamatopoulos, Kostas

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