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Sevov, Marie
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Publications (10 of 10) Show all publications
Berggren, D. M., Folkvaljon, Y., Engvall, M., Sundberg, J., Lambe, M., Antunovic, P., . . . Ejerblad, E. (2018). Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register. British Journal of Haematology, 181(5), 614-627
Open this publication in new window or tab >>Prognostic scoring systems for myelodysplastic syndromes (MDS) in a population-based setting: a report from the Swedish MDS register
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2018 (English)In: British Journal of Haematology, ISSN 0007-1048, E-ISSN 1365-2141, Vol. 181, no 5, p. 614-627Article in journal (Refereed) Published
Abstract [en]

The myelodysplastic syndromes (MDS) have highly variable outcomes and prognostic scoring systems are important tools for risk assessment and to guide therapeutic decisions. However, few population-based studies have compared the value of the different scoring systems. With data from the nationwide Swedish population-based MDS register we validated the International Prognostic Scoring System (IPSS), revised IPSS (IPSS-R) and the World Health Organization (WHO) Classification-based Prognostic Scoring System (WPSS). We also present population-based data on incidence, clinical characteristics including detailed cytogenetics and outcome from the register. The study encompassed 1329 patients reported to the register between 2009 and 2013, 14% of these had therapy-related MDS (t-MDS). Based on the MDS register, the yearly crude incidence of MDS in Sweden was 2<bold></bold>9 per 100000 inhabitants. IPSS-R had a significantly better prognostic power than IPSS (P<0<bold></bold>001). There was a trend for better prognostic power of IPSS-R compared to WPSS (P=0<bold></bold>05) and for WPSS compared to IPSS (P=0<bold></bold>07). IPSS-R was superior to both IPSS and WPSS for patients aged 70years. Patients with t-MDS had a worse outcome compared to de novo MDS (d-MDS), however, the validity of the prognostic scoring systems was comparable for d-MDS and t-MDS. In conclusion, population-based studies are important to validate prognostic scores in a real-world' setting. In our nationwide cohort, the IPSS-R showed the best predictive power.

Place, publisher, year, edition, pages
John Wiley & Sons, 2018
Keywords
myelodysplastic syndrome, International Prognostic Scoring System, revised International Prognostic Scoring System, WHO Classification-based Prognostic Scoring System, therapy-related myelodysplastic syndrome
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-357712 (URN)10.1111/bjh.15243 (DOI)000433333100007 ()29707769 (PubMedID)
Available from: 2018-09-26 Created: 2018-09-26 Last updated: 2018-09-26Bibliographically approved
Bhoi, S., Baliakas, P., Cortese, D., Mattsson, M., Sevov, M., Smedby, K. E., . . . Mansouri, L. (2016). UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia? [Letter to the editor]. Haematologica, 101(2), E63-E65
Open this publication in new window or tab >>UGT2B17 expression: a novel prognostic marker within IGHV-mutated chronic lymphocytic leukemia?
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2016 (English)In: Haematologica, ISSN 0390-6078, E-ISSN 1592-8721, Vol. 101, no 2, p. E63-E65Article in journal, Letter (Refereed) Published
Keywords
CLL; UGT2B17; prognostic markers
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-271300 (URN)10.3324/haematol.2015.136440 (DOI)000379156300007 ()26589911 (PubMedID)
Available from: 2016-01-07 Created: 2016-01-07 Last updated: 2019-04-01
Sevov, M., Bunikis, I., Häggqvist, S., Höglund, M., Rosenquist, R., Ameur, A. & Cavelier, L. (2014). Targeted RNA Sequencing Assay Efficiently Identifies Cryptic KMT2A (MLL)-Fusions in Acute Leukemia Patients. Paper presented at 56th Annual Meeting of the American-Society-of-Hematology, DEC 06-09, 2014, San Francisco, CA. Blood, 124(21)
Open this publication in new window or tab >>Targeted RNA Sequencing Assay Efficiently Identifies Cryptic KMT2A (MLL)-Fusions in Acute Leukemia Patients
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2014 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 124, no 21Article in journal, Meeting abstract (Other academic) Published
National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-247856 (URN)000349233808076 ()
Conference
56th Annual Meeting of the American-Society-of-Hematology, DEC 06-09, 2014, San Francisco, CA
Available from: 2015-03-27 Created: 2015-03-24 Last updated: 2017-12-04Bibliographically approved
Sevov, M., Rosenquist, R. & Mansouri, L. (2012). RNA-based markers as prognostic factors in chronic lymphocytic leukemia. Expert Review of Hematology, 5(1), 69-79
Open this publication in new window or tab >>RNA-based markers as prognostic factors in chronic lymphocytic leukemia
2012 (English)In: Expert Review of Hematology, ISSN 1747-4086, E-ISSN 1747-4094, Vol. 5, no 1, p. 69-79Article, review/survey (Refereed) Published
Abstract [en]

Chronic lymphocytic leukemia (CLL) is most often indolent at diagnosis but has a highly variable clinical course, and many patients will eventually progress and require treatment. Currently, there are a number of clinical and molecular markers known to be predictive of prognosis in CLL that can be applied to discriminate patients that are more likely to develop a progressive disease. Gene-expression profiling studies have identified genes with differential expression between prognostic subgroups in CLL, and research on these RNA-based prognostic markers has expanded during recent years. For example, high lipoprotein lipase and CLLU1 mRNA expression have recently been shown to be strong markers of poor clinical outcome. In this review we will provide a summary of the most significant prognostic markers in CLL, focusing on the recent category of RNA-based markers in particular.

Keywords
CLL, CLLU1, LPL, microRNA, RNA-based prognostic marker, TCL1A, ZAP70
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-170308 (URN)10.1586/EHM.11.80 (DOI)000300266400015 ()
Available from: 2012-03-12 Created: 2012-03-11 Last updated: 2017-12-07Bibliographically approved
Kaderi, M. A., Kanduri, M., Buhl, A. M., Sevov, M., Cahill, N., Gunnarsson, R., . . . Rosenquist, R. (2011). LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia. Haematologica (online), 96(8), 1153-1160
Open this publication in new window or tab >>LPL is the strongest prognostic factor in a comparative analysis of RNA-based markers in early chronic lymphocytic leukemia
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2011 (English)In: Haematologica (online), ISSN 0390-6078, E-ISSN 1592-8721, Vol. 96, no 8, p. 1153-1160Article in journal (Refereed) Published
Abstract [en]

BACKGROUND:

The expression levels of LPL, ZAP70, TCL1A, CLLU1 and MCL1 have recently been proposed as prognostic factors in chronic lymphocytic leukemia. However, few studies have systematically compared these different RNA-based markers.

DESIGN AND METHODS:

Using real-time quantitative PCR, we measured the mRNA expression levels of these genes in unsorted samples from 252 newly diagnosed chronic lymphocytic leukemia patients and correlated our data with established prognostic markers (for example Binet stage, CD38, IGHV gene mutational status and genomic aberrations) and clinical outcome.

RESULTS:

High expression levels of all RNA-based markers, except MCL1, predicted shorter overall survival and time to treatment, with LPL being the most significant. In multivariate analysis including the RNA-based markers, LPL expression was the only independent prognostic marker for overall survival and time to treatment. When studying LPL expression and the established markers, LPL expression retained its independent prognostic strength for overall survival. All of the RNA-based markers, albeit with varying ability, added prognostic information to established markers, with LPL expression giving the most significant results. Notably, high LPL expression predicted a worse outcome in good-prognosis subgroups, such as patients with mutated IGHV genes, Binet stage A, CD38 negativity or favorable cytogenetics. In particular, the combination of LPL expression and CD38 could further stratify Binet stage A patients.

CONCLUSIONS:

LPL expression is the strongest RNA-based prognostic marker in chronic lymphocytic leukemia that could potentially be applied to predict outcome in the clinical setting, particularly in the large group of patients with favorable prognosis.

National Category
Medical and Health Sciences Medical Genetics Cancer and Oncology
Research subject
Clinical Genetics; Medical Genetics; Oncology
Identifiers
urn:nbn:se:uu:diva-111078 (URN)10.3324/haematol.2010.039396 (DOI)000294722700013 ()21508119 (PubMedID)
Available from: 2009-12-02 Created: 2009-12-02 Last updated: 2018-01-12Bibliographically approved
Mansouri, M. R., Sevov, M., Åleskog, A., Jondal, M., Merup, M., Sundström, C., . . . Rosenquist, R. (2010). IGHV3-21 gene usage is associated with high TCL1 expression in chronic lymphocytic leukemia. European Journal of Haematology, 84(2), 109-116
Open this publication in new window or tab >>IGHV3-21 gene usage is associated with high TCL1 expression in chronic lymphocytic leukemia
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2010 (English)In: European Journal of Haematology, ISSN 0902-4441, E-ISSN 1600-0609, Vol. 84, no 2, p. 109-116Article in journal (Refereed) Published
Abstract [en]

T-cell leukemia/lymphoma protein 1 (TCL1) was recently shown to display an expression pattern in chronic lymphocytic leukemia (CLL) corresponding to molecular subtypes, where poor-risk patients demonstrated higher expression levels. Here, we examined the mRNA expression pattern of TCL1 in 144 patients with CLL, including 67 immunoglobulin heavy-chain variable (IGHV) mutated, 58 IGHV unmutated and 19 patients with IGHV3-21 usage. A higher TCL1 expression level was detected in patients with CLL with unmutated vs. mutated IGHV genes (P < 0.001), whereas no difference was demonstrated within the IGHV3-21 cohort (i.e., mutated vs. unmutated and stereotyped vs. non-stereotyped complementarity determining region 3). The IGHV3-21 subgroup displayed high TCL1 mRNA expression, differing significantly from other IGHV mutated cases (P < 0.001), although 11/19 had mutated IGHV genes. Furthermore, high TCL1 expression levels were associated with significantly shorter overall survival (P < 0.001). Altogether, we show that TCL1 mRNA expression may predict clinical outcome in CLL and that the IGHV3-21 subset, regardless of mutational status, displays high TCL1 expression.

National Category
Hematology
Identifiers
urn:nbn:se:uu:diva-121110 (URN)10.1111/j.1600-0609.2009.01369.x (DOI)000273301600003 ()19889012 (PubMedID)
Available from: 2010-03-18 Created: 2010-03-18 Last updated: 2019-04-01
Mansouri, M., Sevov, M., Fahlgren, E., Tobin, G., Jondal, M., Osorio, L., . . . Rosenquist, R. (2010). Lipoprotein lipase is differentially expressed in prognostic subsets of chronic lymphocytic leukemia but displays invariably low catalytical activity. Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, 34(3), 301-306
Open this publication in new window or tab >>Lipoprotein lipase is differentially expressed in prognostic subsets of chronic lymphocytic leukemia but displays invariably low catalytical activity
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2010 (English)In: Leukemia research: a Forum for Studies on Leukemia and Normal Hemopoiesis, ISSN 0145-2126, E-ISSN 1873-5835, Vol. 34, no 3, p. 301-306Article in journal (Refereed) Published
Abstract [en]

Lipoprotein lipase (LPL) expression has been shown to correlate with IGHV mutational status and to predict outcome in chronic lymphocytic leukemia (CLL). We here investigated the prognostic impact of LPL expression in relation to other prognostic markers including IGHV3-21 usage in 140 CLL patients. Additionally, we studied the catalytic activity of LPL in CLL cells. A significant difference in LPL mRNA expression was detected in IGHV unmutated compared to mutated CLL patients (p<0.001). However, the poor-prognostic mutated/stereotyped IGHV3-21 patients did not differ from other mutated CLL cases. Clinical outcome was significantly different in CLL cases with high versus low LPL expression (p<0.001), and LPL expression exceeded mutation status/IGHV3-21 usage as an independent prognostic marker. Finally, LPL protein expression correlated significantly with mRNA expression and was higher in IGHV unmutated versus mutated CLL (p=0.018), although the majority of synthesized protein was catalytically inactive indicating a non-catalytical function in CLL.

Keywords
LPL expression, LPL catalytical activity, IGHV mutational status, IGHV3 21 usage, Chronic lymphocytic leukemia, Prognosis
National Category
Cancer and Oncology Hematology
Identifiers
urn:nbn:se:uu:diva-121105 (URN)10.1016/j.leukres.2009.07.032 (DOI)000274529600008 ()19709746 (PubMedID)
Available from: 2010-03-18 Created: 2010-03-18 Last updated: 2019-04-01Bibliographically approved
Sevov, M. (2010). RNA-based Prognostic Markers in Chronic Lymphocytic Leukemia. (Doctoral dissertation). Uppsala: Acta Universitatis Upsaliensis
Open this publication in new window or tab >>RNA-based Prognostic Markers in Chronic Lymphocytic Leukemia
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease where a significant proportion of patients will develop an aggressive disease. Today, the mutational status of the immunoglobulin heavy variable (IGHV) genes is one of the strongest prognostic markers in CLL, where unmutated IGHV genes correlate with poor outcome. In addition, IGHV3-21 gene usage is associated with poor prognosis independent of mutational status. Recently, several genes were shown to be differently expressed between IGHV mutated and unmutated CLL and were suggested as prognostic markers. The aim of this thesis was to examine the applicability of these RNA-based prognostic markers in CLL.

In papers I and II, the prognostic significance of LPL and TCL1A mRNA expression in CLL was investigated in 140 and 144 patients, respectively. High expression was found to be associated with inferior clinical outcome for both markers. However, CLL cases with mutated IGHV3-21 genes displayed low levels of LPL expression, indicating that LPL cannot identify this poor-risk patient group. In contrast, high TCL1A expression was detected in all IGHV3-21 cases. To elucidate the functionality of LPL in CLL, LPL lipase activity was measured in 33 cases. The lipase activity was found to be invariably low, implying an alternative function for LPL in CLL.

In paper III, a comprehensive analysis of five RNA-based markers (LPL, TCL1A, ZAP70, CLLU1 and MCL1) was performed in 252 CLL patients. All RNA-based markers except MCL1 predicted clinical outcome, with LPL being the strongest. Moreover, LPL expression independently predicted overall survival when adjusted for established markers. All of the RNA-based markers added additional prognostic information to established markers, e.g. high LPL expression predicted an inferior outcome in patients with mutated IGHV genes or good-risk cytogenetics.

For clinical application, over time stability of prognostic markers is crucial. In paper IV, the expression of LPL, TCL1A, ZAP70 and MCL1 was investigated in samples taken at diagnosis and at a follow-up of seven years in 104 CLL patients. LPL was found to be the most stable marker, displaying high correlation between the sequential samples, whereas ZAP70 and MCL1 varied significantly. TCL1A expression increased at follow-up, which may indicate disease progression as TCL1A promotes cell survival.

In summary, this thesis highlights the applicability of RNA-based markers in CLL prognostication, both as single markers or in combination with established markers. In particular, LPL was shown to be the strongest RNA-based marker in terms of prognostic strength and stability.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. p. 79
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 624
Keywords
Chronic lymphocytic leukemia, prognostic markers, RNA-based markers, LPL
National Category
Medical Genetics Hematology
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-133250 (URN)978-91-554-7950-3 (ISBN)
Public defence
2010-12-17, Rudbecksalen, Rudbecklaboratoriet, Dag Hammarskjöldsväg 20, Uppsala, 13:00 (English)
Opponent
Supervisors
Funder
Available from: 2010-11-25 Created: 2010-11-04 Last updated: 2018-01-12Bibliographically approved
Wetterbom, A., Sevov, M., Cavelier, L. & Bergström, T. (2006). Comparative genomic analysis of human and chimpanzee indicates a key role for indels in primate evolution. Journal of Molecular Evolution, 63(5), 682-690
Open this publication in new window or tab >>Comparative genomic analysis of human and chimpanzee indicates a key role for indels in primate evolution
2006 (English)In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 63, no 5, p. 682-690Article in journal (Refereed) Published
Abstract [en]

Sequence comparison of humans and chimpanzees is of interest to understand the mechanisms behind primate evolution. Here we present an independent analysis of human chromosome 21 and the high-quality BAC clone sequences of the homologous chimpanzee chromosome 22. In contrast to previous studies, we have used global alignment methods and Ensembl predictions of protein coding genes (n = 224) for the analysis. Divergence due to insertions and deletions (indels) along with substitutions was examined separately for different genomic features (coding, noncoding genic, and intergenic sequence). The major part of the genomic divergence could be attributed to indels (5.07%), while the nucleotide divergence was estimated as 1.52%. Thus the total divergence was estimated as 6.58%. When excluding repeats and low-complexity DNA the total divergence decreased to 2.37%. The chromosomal distribution of nucleotide substitutions and indel events was significantly correlated. To further examine the role of indels in primate evolution we focused on coding sequences. Indels were found within the coding sequence of 13% of the genes and approximately half of the indels have not been reported previously. In 5% of the chimpanzee genes, indels or substitutions caused premature stop codons that rendered the affected transcripts nonfunctional. Taken together, our findings demonstrate that indels comprise the majority of the genomic divergence. Furthermore, indels occur frequently in coding sequences. Our results thereby support the hypothesis that indels may have a key role in primate evolution.

Keywords
indels, comparative genomics, chimpanzee, primate evolution
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-10256 (URN)10.1007/s00239-006-0045-7 (DOI)000242014800010 ()17075697 (PubMedID)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-11Bibliographically approved
Sevov, M., Elfineh, L. & Cavelier, L. B. (2006). Resveratrol regulates the expression of LXR-alpha in human macrophages. Biochemical and Biophysical Research Communications - BBRC, 348(3), 1047-1054
Open this publication in new window or tab >>Resveratrol regulates the expression of LXR-alpha in human macrophages
2006 (English)In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 348, no 3, p. 1047-1054Article in journal (Refereed) Published
Abstract [en]

The naturally occurring polyphenol resveratrol has been associated with the beneficial effects of red wine consumption on cardiovascular disease and shown to inhibit atherosclerosis in animal models. To determine if resveratrol affects the expression of genes that control lipid homeostasis in human macrophages, we measured expression changes in the LXR-alpha pathway, crucial to cholesterol efflux, and in genes that mediate lipoprotein uptake. Resveratrol treatment of THP-1 macrophages induced LXR-alpha at mRNA and protein levels. Increased recruitment of RNA polymerase 11 to the LXR-alpha promoter suggested that up-regulation was at least partly mediated by transcriptional mechanisms. Resveratrol also induced LXR-alpha in human monocyte-derived macrophages together with elevated ABCAI and ABCGI mRNA levels. Moreover, resveratrol repressed the expression of the lipid uptake genes LPL and SR-All. The ability of resveratrol to modulate expression of the genes involved in lipid uptake and efflux suggests that polyphenols can potentially limit cholesterol accumulation in human macrophages.

Keywords
LXR-alpha, THP-1, macrophages, resveratrol, chromatin immunoprecipitation, gene regulation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-10546 (URN)10.1016/j.bbrc.2006.07.155 (DOI)000240166500037 ()16901463 (PubMedID)
Available from: 2007-04-02 Created: 2007-04-02 Last updated: 2017-12-11Bibliographically approved
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