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- Kontopoulos, Efstratios, et al.
(författare)
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Studying the Cohesion Evolution of Genes Related to Chronic Lymphocytic Leukemia Using Semantic Similarity in Gene Ontology and Self-Organizing Maps
- 2016
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Ingår i: Proceedings of SWAT4LS-16, 9th International Conference on Semantic Web Applications and Tools for Life Sciences.
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Konferensbidrag (refereegranskat)abstract
- A significant body of work on biomedical text mining is aimed at uncovering meaningful associations between biological entities, including genes. This has the potential to offer new insights for research, uncovering hidden links between genes involved in critical pathways and processes. Recently, high-throughput studies have started to unravel the genetic landscape of chronic lymphocytic leukemia (CLL), the most common adult leukemia. CLL displays remarkable clinical heterogeneity, likely reflecting its underlying biological heterogeneity which, despite all progress, still remains insufficiently characterized and understood. This paper deploys an ontology-based semantic similarity combined with self-organizing maps for studying the temporal evolution of cohesion among CLL-related genes and the extracted information. Three consecutive time periods are considered and groups of genes are derived therein. Our preliminary results indicated that our proposed gene groupings are meaningful and that the temporal dimension indeed impacted the gene cohesion, leaving a lot of room for further promising investigations.
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| 3. |
- Papakonstantinou, Nikos, et al.
(författare)
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The histone methyltransferase EZH2 as a novel prosurvival factor in clinically aggressive chronic lymphocytic leukemia
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:24, s. 35946-35959
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Tidskriftsartikel (refereegranskat)abstract
- The histone methyltransferase EZH2 induces gene repression through trimethylation of histone H3 at lysine 27 (H3K27me3). EZH2 overexpression has been reported in many types of cancer and associated with poor prognosis. Here we investigated the expression and functionality of EZH2 in chronic lymphocytic leukemia (CLL). Aggressive cases with unmutated IGHV genes (U-CLL) displayed significantly higher EZH2 expression compared to indolent CLL cases with mutated IGHV genes (M-CLL); furthermore, in U-CLL EZH2 expression was upregulated with disease progression. Within U-CLL, EZH2(high) cases harbored significantly fewer (p = 0.033) TP53 gene abnormalities compared to EZH2(low) cases. EZH2(high) cases displayed high H3K27me3 levels and increased viability suggesting that EZH2 is functional and likely confers a survival advantage to CLL cells. This argument was further supported by siRNA-mediated downmodulation of EZH2 which resulted in increased apoptosis. Notably, at the intraclonal level, cell proliferation was significantly associated with EZH2 expression. Treatment of primary CLL cells with EZH2 inhibitors induced downregulation of H3K27me3 levels leading to increased cell apoptosis. In conclusion, EZH2 is overexpressed in adverse-prognosis CLL and associated with increased cell survival and proliferation. Pharmacologic inhibition of EZH2 catalytic activity promotes apoptosis, highlighting EZH2 as a novel potential therapeutic target for specific subgroups of patients with CLL.
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| 4. |
- Sutton, Lesley-Ann, et al.
(författare)
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Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors
- 2016
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Ingår i: Haematologica. - : Ferrata Storti Foundation (Haematologica). - 0390-6078 .- 1592-8721. ; 101:8, s. 959-967
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Tidskriftsartikel (refereegranskat)abstract
- We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets# 2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).
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