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UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia?
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
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2016 (Engelska)Ingår i: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, nr 2, s. E63-E65Artikel i tidskrift, Letter (Refereegranskat) Published
Ort, förlag, år, upplaga, sidor
2016. Vol. 101, nr 2, s. E63-E65
Nyckelord [en]
CLL; UGT2B17; prognostic markers
Nationell ämneskategori
Hematologi
Identifikatorer
URN: urn:nbn:se:uu:diva-271300DOI: 10.3324/haematol.2015.136440ISI: 000379156300007PubMedID: 26589911OAI: oai:DiVA.org:uu-271300DiVA, id: diva2:891602
Tillgänglig från: 2016-01-07 Skapad: 2016-01-07 Senast uppdaterad: 2019-04-01
Ingår i avhandling
1. Prognostic markers and DNA methylation profiling in lymphoid malignancies
Öppna denna publikation i ny flik eller fönster >>Prognostic markers and DNA methylation profiling in lymphoid malignancies
2017 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

In recent years, great progress has been achieved towards identifying novel biomarkers in lymphoid malignancies, including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), at the genomic, transcriptomic and epigenomic level for accurate risk-stratification and prediction of treatment response. In paper I, we validated the prognostic relevance of a recently proposed RNA-based marker in CLL, UGT2B17, and analyzed its expression levels in 253 early-stage patients. Besides confirming its prognostic impact in multivariate analysis, we could identify 30% of IGHV-mutated CLL (M-CLL) cases with high expression and poor outcome, which otherwise lacked any other poor-prognostic marker. In paper II, we investigated the prognostic impact of a previously reported 5 CpG signature that divides CLL patients into three clinico-biological subgroups, namely naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL) and intermediate CLL (i-CLL), in 135 CLL patients using pyrosequencing. We validated the signature as an independent marker in multivariate analysis and further reported that subset #2 cases were predominantly classified as i-CLL, although displaying a similar outcome as n-CLL. In paper III, we investigated the methylation status and expression level of miR26A1 in both CLL (n=70) and MCL (n=65) cohorts. High miR26A1 methylation was associated with IGHV-unmutated (U-CLL) and shorter overall survival (OS) in CLL, while it was uniformly hypermethylated in MCL. Furthermore, overexpression of miR26A1 resulted in significant downregulation of EZH2 that in turn led to increased apoptosis. In paper IV, we performed DNA methylation profiling in 176 CLL cases assigned to one of 8 major stereotyped subsets (#1-8) in relation to non-subset CLL (n=325) and different normal B-cell subpopulations. Principal component analysis of subset vs. non-subset CLL revealed that U-CLL and M-CLL subsets generally clustered with n-CLL and m-CLL, respectively, indicating common cellular origins. In contrast, subset #2 emerged as the first defined member of the i-CLL subgroup, which in turn alludes to a distinct cellular origin for subset #2 and i-CLL patients. Altogether, this thesis confirms the prognostic significance of RNA and epigenetic-based markers in CLL, provides insight into the mechanism of miRNA deregulation in lymphoid malignancies and further unravels the DNA methylation landscape in stereotyped subsets of CLL.

 

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2017. s. 77
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1363
Nyckelord
Lymphoid malignancies, CLL, MCL, prognostic markers, micro-RNA, methylation, stereotyped subsets
Nationell ämneskategori
Hematologi
Identifikatorer
urn:nbn:se:uu:diva-328616 (URN)978-91-513-0053-5 (ISBN)
Disputation
2017-10-19, Rudbecksalen, Dag Hammarskjölds väg 20, Uppsala, 09:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2017-09-26 Skapad: 2017-08-28 Senast uppdaterad: 2017-10-17

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Experimentell och klinisk onkologiHematologiMedicinsk genetik och genomikInstitutionen för medicinska vetenskaper
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