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Larsson, Pär
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Publications (10 of 14) Show all publications
Haider, Z., Larsson, P., Landfors, M., Köhn, L., Schmiegelow, K., Flaegstad, T., . . . Degerman, S. (2019). An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression. Cancer Medicine, 8(1), 311-324
Open this publication in new window or tab >>An integrated transcriptome analysis in T-cell acute lymphoblastic leukemia links DNA methylation subgroups to dysregulated TAL1 and ANTP homeobox gene expression
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2019 (English)In: Cancer Medicine, ISSN 2045-7634, E-ISSN 2045-7634, Vol. 8, no 1, p. 311-324Article in journal (Refereed) Published
Abstract [en]

Classification of pediatric T‐cell acute lymphoblastic leukemia (T‐ALL) patients into CIMP (CpG Island Methylator Phenotype) subgroups has the potential to improve current risk stratification. To investigate the biology behind these CIMP subgroups, diagnostic samples from Nordic pediatric T‐ALL patients were characterized by genome‐wide methylation arrays, followed by targeted exome sequencing, telomere length measurement, and RNA sequencing. The CIMP subgroups did not correlate significantly with variations in epigenetic regulators. However, the CIMP+ subgroup, associated with better prognosis, showed indicators of longer replicative history, including shorter telomere length (P = 0.015) and older epigenetic (P < 0.001) and mitotic age (P < 0.001). Moreover, the CIMP+ subgroup had significantly higher expression of ANTP homeobox oncogenes, namely TLX3, HOXA9, HOXA10, and NKX2‐1, and novel genes in T‐ALL biology including PLCB4, PLXND1, and MYO18B. The CIMP− subgroup, with worse prognosis, was associated with higher expression of TAL1 along with frequent STIL‐TAL1 fusions (2/40 in CIMP+ vs 11/24 in CIMP−), as well as stronger expression of BEX1. Altogether, our findings suggest different routes for leukemogenic transformation in the T‐ALL CIMP subgroups, indicated by different replicative histories and distinct methylomic and transcriptomic profiles. These novel findings can lead to new therapeutic strategies.

Place, publisher, year, edition, pages
John Wiley & Sons, 2019
Keywords
BEX1, DNA methylation, HOXA, pediatric acute lymphoblastic leukemia, TAL1
National Category
Cancer and Oncology Hematology Pediatrics Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:umu:diva-156637 (URN)10.1002/cam4.1917 (DOI)000456858100032 ()30575306 (PubMedID)
Funder
The Kempe FoundationsSwedish Childhood Cancer FoundationVästerbotten County CouncilSwedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2019-02-20 Created: 2019-02-20 Last updated: 2019-02-20Bibliographically approved
Borssén, M., Nordlund, J., Haider, Z., Landfors, M., Larsson, P., Kanerva, J., . . . Degerman, S. (2018). DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia. Clinical Epigenetics, 10, Article ID 31.
Open this publication in new window or tab >>DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia
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2018 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 31Article in journal (Refereed) Published
Abstract [en]

Background: Few biological markers are associated with survival after relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). In pediatric T-cell ALL, we have identified promoter-associated methylation alterations that correlate with prognosis. Here, the prognostic relevance of CpG island methylation phenotype (CIMP) classification was investigated in pediatric BCP-ALL patients.

Methods: Six hundred and one BCP-ALL samples from Nordic pediatric patients (age 1-18) were CIMP classified at initial diagnosis and analyzed in relation to clinical data.

Results: Among the 137 patients that later relapsed, patients with a CIMP-profile (n = 42) at initial diagnosis had an inferior overall survival (pOS(5years) 33%) compared to CIMP+ patients (n = 95, pOS(5years) 65%) (p = 0.001), which remained significant in a Cox proportional hazards model including previously defined risk factors.

Conclusion: CIMP classification is a strong candidate for improved risk stratification of relapsed BCP-ALL.

Place, publisher, year, edition, pages
BioMed Central, 2018
Keywords
DNA methylation, BCP-ALL, prognosis, CIMP, relapse, risk stratification
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-146216 (URN)10.1186/s13148-018-0466-3 (DOI)000427080200001 ()29515676 (PubMedID)
Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2019-02-20Bibliographically approved
Norberg, A., Rosén, A., Raaschou-Jensen, K., Kjeldsen, L., Moilanen, J. S., Paulsson-Karisson, Y., . . . Hultdin, M. (2018). Novel variants in Nordic patients referred for genetic testing of telomere-related disorders. European Journal of Human Genetics, 26(6), 858-867
Open this publication in new window or tab >>Novel variants in Nordic patients referred for genetic testing of telomere-related disorders
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2018 (English)In: European Journal of Human Genetics, ISSN 1018-4813, E-ISSN 1476-5438, Vol. 26, no 6, p. 858-867Article in journal (Refereed) Published
Abstract [en]

Telomere-related disorders are a clinically and genetically heterogeneous group of disorders characterized by premature telomere shortening and proliferative failure of a variety of tissues. This study reports the spectrum of telomere-related gene variants and telomere length in Nordic patients referred for genetic testing due to suspected telomere-related disorder. We performed Sanger sequencing of the genes TERT, TERC, DKC1, and TINF2 on 135 unrelated index patients and measured telomere length by qPCR on DNA from peripheral blood leukocytes. We identified pathogenic or likely pathogenic variants in 10 index patients, all of which had short telomeres compared to age-matched healthy controls. Six of the 10 variants were novel; three in TERC (n.69_74dupAGGCGC, n.122_125delGCGG, and n.407_408delinsAA) and three in TERT (p.(D684G), p.(R774*), and p.(*1133Wext*39)). The high proportion of novel variants identified in our study highlights the need for solid interpretation of new variants that may be detected. Measurement of telomere length is a useful approach for evaluating pathogenicity of genetic variants associated with telomere-related disorders.

Place, publisher, year, edition, pages
Nature Publishing Group, 2018
National Category
Medical Genetics
Identifiers
urn:nbn:se:umu:diva-149013 (URN)10.1038/s41431-018-0112-8 (DOI)000433424200010 ()29483670 (PubMedID)2-s2.0-85042538231 (Scopus ID)
Available from: 2018-06-15 Created: 2018-06-15 Last updated: 2018-06-15Bibliographically approved
Eklöf, V., Löfgren-Burström, A., Zingmark, C., Edin, S., Larsson, P., Karling, P., . . . Palmqvist, R. (2017). Cancer-associated fecal microbial markers in colorectal cancer detection. International Journal of Cancer, 141(12), 2528-2536
Open this publication in new window or tab >>Cancer-associated fecal microbial markers in colorectal cancer detection
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2017 (English)In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 141, no 12, p. 2528-2536Article in journal (Refereed) Published
Abstract [en]

Colorectal cancer (CRC) is the second most common cause of cancer death in the western world. An effective screening program leading to early detection of disease would severely reduce the mortality of CRC. Alterations in the gut microbiota have been linked to CRC, but the potential of microbial markers for use in CRC screening has been largely unstudied. We used a nested case-control study of 238 study subjects to explore the use of microbial markers for clbA+ bacteria harboring the pks pathogenicity island, afa-C+ diffusely adherent Escherichia coli harboring the afa-1 operon, and Fusobacterium nucleatum in stool as potential screening markers for CRC. We found that individual markers for clbA+ bacteria and F. nucleatum were more abundant in stool of patients with CRC, and could predict cancer with a relatively high specificity (81.5% and 76.9%, respectively) and with a sensitivity of 56.4% and 69.2%, respectively. In a combined test of clbA+ bacteria and F. nucleatum, CRC was detected with a specificity of 63.1% and a sensitivity of 84.6%. Our findings support a potential value of microbial factors in stool as putative noninvasive biomarkers for CRC detection. We propose that microbial markers may represent an important future screening strategy for CRC, selecting patients with a "high-risk" microbial pattern to other further diagnostic procedures such as colonoscopy.

Place, publisher, year, edition, pages
John Wiley & Sons, 2017
Keywords
F. nucleatum, clbA, colorectal cancer, gut microbiota, screening, stool
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-142380 (URN)10.1002/ijc.31011 (DOI)000413549900019 ()28833079 (PubMedID)
Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2019-01-02Bibliographically approved
Ling, A., Löfgren-Burström, A., Larsson, P., Li, X., Wikberg, M. L., Öberg, Å., . . . Palmqvist, R. (2017). TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer. Oncoimmunology, 6(11), Article ID e1356143.
Open this publication in new window or tab >>TAP1 down-regulation elicits immune escape and poor prognosis in colorectal cancer
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2017 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 11, article id e1356143Article in journal (Refereed) Published
Abstract [en]

The anti-tumor immune response has been shown to be of great prognostic importance in colorectal cancer (CRC) and so has the tumors ability for immune evasion. Our aim of this study was to investigate tumor factors that influence immunity. We used a gene expression array to search for potential mechanisms of tumor immune escape. One candidate gene identified was TAP1, involved in antigen presentation by MHC class I. TAP1 protein expression was evaluated by immunohistochemistry in 436 CRC patients of the Colorectal Cancer in Umeå Study cohort. We found a significant association between a downregulated expression of TAP1 and low infiltration of various subtypes of lymphocytes as well as macrophages. A downregulated expression of TAP1 was further found to be independent of molecular characteristics, suggesting TAP1 down-regulation to reach beyond the well described highly immunogenic MSI CRCs. A low expression of TAP1 was also significantly associated with poor prognosis in patients with CRC, a result that stayed significant in tumor front of early stage tumors (stage I-II) through multivariable analyses. Furthermore, we found that TAP1 expression was inversely correlated with methylation at sites in close proximity to the promoter region. In summary, our results show down-regulation of TAP1 to be a general mechanism of tumor immune escape in CRC and a poor prognostic factor in stage I-II CRC patients. We also suggest that methylation of the TAP1 gene may be a putative mechanism for TAP1 downregulation.

Keywords
TAP1, antigen presentation, colorectal cancer, immune escape, prognosis
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-142377 (URN)10.1080/2162402X.2017.1356143 (DOI)000414522400004 ()29147604 (PubMedID)
Funder
Swedish Cancer Society, CAN 2014/858Västerbotten County Council, VLL-463871
Available from: 2017-11-29 Created: 2017-11-29 Last updated: 2018-11-13Bibliographically approved
Bergqvist, J., Forsman, O., Larsson, P., Näslund, J., Lilja, T., Engdahl, C., . . . Bucht, G. (2015). Detection and Isolation of Sindbis Virus from Mosquitoes Captured During an Outbreak in Sweden, 2013. Vector Borne and Zoonotic Diseases, 15(2), 133-140
Open this publication in new window or tab >>Detection and Isolation of Sindbis Virus from Mosquitoes Captured During an Outbreak in Sweden, 2013
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2015 (English)In: Vector Borne and Zoonotic Diseases, ISSN 1530-3667, E-ISSN 1557-7759, Vol. 15, no 2, p. 133-140Article in journal (Refereed) Published
Abstract [en]

Mosquito-borne alphaviruses have the potential to cause large outbreaks throughout the world. Here we investigated the causative agent of an unexpected Sindbis virus (SINV) outbreak during August-September, 2013, in a previously nonendemic region of Sweden. Mosquitoes were collected using carbon dioxide-baited CDC traps at locations close to human cases. The mosquitoes were initially screened as large pools by SINV-specific quantitative RT-PCR, and the SINV-positive mosquitoes were species determined by single-nucleotide polymorphism (SNP) analysis, followed by sequencing the barcoding region of the cytochrome oxidase I gene. The proportion of the collected mosquitoes was determined by a metabarcoding strategy. By using novel strategies for PCR screening and genetic typing, a new SINV strain, Lovanger, was isolated from a pool of 1600 mosquitoes composed of Culex, Culiseta, and Aedes mosquitoes as determined by metabarcoding. The SINV-positive mosquito Culiseta morsitans was identified by SNP analysis and sequencing. After whole-genome sequencing and phylogenetic analysis, the SINV Lovanger isolate was shown to be most closely similar to recent Finnish SINV isolates. In conclusion, within a few weeks, we were able to detect and isolate a novel SINV strain and identify the mosquito vector during a sudden SINV outbreak.

Keywords
Barcoding, Mosquito, Isolation, Virus, Sindbis
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-100963 (URN)10.1089/vbz.2014.1717 (DOI)000349682500007 ()25700044 (PubMedID)
Available from: 2015-03-18 Created: 2015-03-16 Last updated: 2018-06-07Bibliographically approved
Birdsell, D. N., Johansson, A., Öhrman, C., Kaufman, E., Molins, C., Pearson, T., . . . Wagner, D. M. (2014). Francisella tularensis subsp. tularensis group A.I, United States. Emerging Infectious Diseases, 20(5), 861-865
Open this publication in new window or tab >>Francisella tularensis subsp. tularensis group A.I, United States
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2014 (English)In: Emerging Infectious Diseases, ISSN 1080-6040, E-ISSN 1080-6059, Vol. 20, no 5, p. 861-865Article in journal (Refereed) Published
Abstract [en]

We used whole-genome analysis and subsequent characterization of geographically diverse strains using new genetic signatures to identify distinct subgroups within Francisella tularensis subsp. tularensis group A.I: A.I.3, A.I.8, and A.I.12. These subgroups exhibit complex phylogeographic patterns within North America. The widest distribution was observed for A.I.12, which suggests an adaptive advantage.

National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-100459 (URN)10.3201/eid2005.131559 (DOI)000335124900021 ()24755401 (PubMedID)
Available from: 2015-03-03 Created: 2015-03-03 Last updated: 2018-06-07Bibliographically approved
Sjödin, A., Svensson, K., Öhrman, C., Ahlinder, J., Lindgren, P., Duodu, S., . . . Forsman, M. (2012). Genome characterisation of the genus Francisella reveals insight into similar evolutionary paths in pathogens of mammals and fish. BMC Genomics, 13, 268
Open this publication in new window or tab >>Genome characterisation of the genus Francisella reveals insight into similar evolutionary paths in pathogens of mammals and fish
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2012 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 13, p. 268-Article in journal (Refereed) Published
Abstract [en]

Background: Prior to this study, relatively few strains of Francisella had been genome-sequenced. Previously published Francisella genome sequences were largely restricted to the zoonotic agent F. tularensis. Only limited data were available for other members of the Francisella genus, including F. philomiragia, an opportunistic pathogen of humans, F. noatunensis, a serious pathogen of farmed fish, and other less well described endosymbiotic species. Results: We determined the phylogenetic relationships of all known Francisella species, including some for which the phylogenetic positions were previously uncertain. The genus Francisella could be divided into two main genetic clades: one included F. tularensis, F. novicida, F. hispaniensis and Wolbachia persica, and another included F. philomiragia and F. noatunensis. Some Francisella species were found to have significant recombination frequencies. However, the fish pathogen F. noatunensis subsp. noatunensis was an exception due to it exhibiting a highly clonal population structure similar to the human pathogen F. tularensis. Conclusions: The genus Francisella can be divided into two main genetic clades occupying both terrestrial and marine habitats. However, our analyses suggest that the ancestral Francisella species originated in a marine habitat. The observed genome to genome variation in gene content and IS elements of different species supports the view that similar evolutionary paths of host adaptation developed independently in F. tularensis (infecting mammals) and F. noatunensis subsp. noatunensis (infecting fish).

Keywords
Francisella, Next-generation sequencing, Recombination, Fish, Genetics, Evolution
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:umu:diva-61992 (URN)10.1186/1471-2164-13-268 (DOI)000310708000001 ()
Available from: 2012-12-12 Created: 2012-12-04 Last updated: 2018-06-08Bibliographically approved
Myrtennäs, K., Sjödin, A., Byström, M., Granberg, M., Brittnacher, M. J., Rohmer, L., . . . Johansson, A. (2012). Genome sequence of Francisella Tularensis subspecies holarctica Strain FSC200, isolated from a child with Tularemia. Journal of Bacteriology, 194(24), 6965-6966
Open this publication in new window or tab >>Genome sequence of Francisella Tularensis subspecies holarctica Strain FSC200, isolated from a child with Tularemia
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2012 (English)In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 194, no 24, p. 6965-6966Article in journal (Refereed) Published
Abstract [en]

Here we report the complete, accurate 1.89-Mb genome sequence of Francisella tularensis subsp. holarctica strain FSC200, isolated in 1998 in the Swedish municipality Ljusdal, which is in an area where tularemia is highly endemic. This genome is important because strain FSC200 has been extensively used for functional and genetic studies of Francisella and is well-characterized.

Place, publisher, year, edition, pages
American Society for Microbiology, 2012
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-63765 (URN)10.1128/JB.01040-12 (DOI)000311922800051 ()23209222 (PubMedID)
Available from: 2013-01-14 Created: 2013-01-07 Last updated: 2018-06-08Bibliographically approved
Johansson, A., Celli, J., Conlan, W., Elkins, K. L., Forsman, M., Keim, P. S., . . . Sjöstedt, A. (2010). Objections to the transfer of Francisella novicida to the subspecies rank of Francisella tularensis. International Journal of Systematic and Evolutionary Microbiology, 60(8), 1717-1718
Open this publication in new window or tab >>Objections to the transfer of Francisella novicida to the subspecies rank of Francisella tularensis
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2010 (English)In: International Journal of Systematic and Evolutionary Microbiology, ISSN 1466-5026, E-ISSN 1466-5034, Vol. 60, no 8, p. 1717-1718Article in journal (Refereed) Published
Keywords
diversity; names
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-42619 (URN)10.1099/ijs.0.022830-0 (DOI)000281175700001 ()20688748 (PubMedID)
Available from: 2011-04-11 Created: 2011-04-11 Last updated: 2018-06-08Bibliographically approved
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