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  • 1.
    Borssen, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Cullman, Inger
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sundstrom, Christer
    Porwit, Anna
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia-associations with immunophenotype and cytogenetic subgroup2011In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, no 12, p. 1144-1151Article in journal (Refereed)
    Abstract [en]

    Telomere maintenance, important for long-term cell survival and malignant transformation, is directed by a multitude of factors, including epigenetic mechanisms, and has been implicated in outcomes for patients with leukemia. In the present study, the objective was to investigate the biological and clinical significance of telomere length and promoter methylation of the human telomerase reverse transcriptase gene in childhood acute lymphoblastic leukemia. A cohort of 169 childhood acute lymphoblastic leukemias was investigated for telomere length, human telomerase reverse transcriptase gene promoter methylation status, genomic aberrations, immunophenotype, and clinical outcomes. Methylation of the core promoter of the human telomerase reverse transcriptase (hTERT) gene was demonstrated in 24% of diagnostic samples, with a significant difference between B-cell precursor (n = 130) and T-cell acute lymphoblastic leukemia (ALL) (n = 17) cases (18% and 72%, respectively; p < 0.001). No remission sample demonstrated hTERT promoter methylation (n = 40). Within the B-cell precursor group, t(12;21)(p13;q22) [ETV6/RUNX1] cases (n = 19) showed a much higher frequency of hTERT methylation than high-hyperdiploid (51 61 chromosomes) ALL (n = 44) (63% and 7%, respectively; p < 0.001). hTERT messenger RNA levels were negatively associated with methylation status and, in the t(12;21) group, methylated cases had shorter telomeres (p = 0.017). In low-risk B-cell precursor patients (n = 101), long telomeres indicated a worse prognosis. The collected data from the present study indicate that the telomere biology in childhood ALL has clinical implications and reflects molecular differences between diverse ALL subgroups. (C) 2011 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc.

  • 2.
    Borssen, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Palmqvist, Lars
    Karrman, Kristina
    Abrahamsson, Jonas
    Behrendtz, Mikael
    Heldrup, Jesper
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, p. e65373-Article in journal (Refereed)
    Abstract [en]

    Background: Treatment of pediatric T-cell acute lymphoblastic leukemia (T-ALL) has improved, but there is a considerable fraction of patients experiencing a poor outcome. There is a need for better prognostic markers and aberrant DNA methylation is a candidate in other malignancies, but its potential prognostic significance in T-ALL is hitherto undecided.

    Design and Methods: Genome wide promoter DNA methylation analysis was performed in pediatric T-ALL samples (n = 43) using arrays covering >27000 CpG sites. Clinical outcome was evaluated in relation to methylation status and compared with a contemporary T-ALL group not tested for methylation (n = 32).

    Results: Based on CpG island methylator phenotype (CIMP), T-ALL samples were subgrouped as CIMP+ (high methylation) and CIMP- (low methylation). CIMP- T-ALL patients had significantly worse overall and event free survival (p = 0.02 and p = 0.001, respectively) compared to CIMP+ cases. CIMP status was an independent factor for survival in multivariate analysis including age, gender and white blood cell count. Analysis of differently methylated genes in the CIMP subgroups showed an overrepresentation of transcription factors, ligands and polycomb target genes.

    Conclusions: We identified global promoter methylation profiling as being of relevance for subgrouping and prognostication of pediatric T-ALL.

  • 3.
    Borssén, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    DNA methylation as a prognostic marker i acute lymphoblastic leukemia2016Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Most ALL cases originate from immature B-cells (BCP-ALL) and are characterized by reoccurring structural genetic aberrations. These aberrations hold information of the pathogenesis of ALL and are used for risk stratification in treatment. Despite increased knowledge of genetic aberrations in pediatric T-cell ALL (T-ALL), no reliable molecular genetic markers exist for identifying patients with higher risk of relapse. The lack of molecular prognostic markers is also evident in patients with relapsed ALL. During the last decades, aberrant epigenetic mechanisms including DNA methylation have emerged as important components in cancer development. Telomere maintenance is another important factor in malignant transformation and is crucial for long-term cell survival. Like DNA methylation, telomere length maintenance has also been implicated to reflect outcomes for patients with leukemia.

    In this thesis, the prognostic relevance of DNA methylation and telomere length was investigated in pediatric ALL at diagnosis and relapse. The telomere length (TL) was significantly shorter in diagnostic ALL samples compared to normal bone marrow samples collected at cessation of therapy, reflecting the proliferation associated telomere length shortening. Prognostic relevance of TL was shown in low-risk BCP-ALL patients where longer telomeres at diagnosis were associated with higher risk of relapse.

    Genome-wide methylation characterization by arrays in diagnostic T-ALL samples identified two distinct methylation subgroups denoted CIMP+ (CpG Island Methylator Phenotype high) and CIMP- (low). CIMP- T-ALL patients had significantly worse outcome compared to CIMP+ cases. These results were confirmed in a Nordic cohort treated according to the current NOPHO-ALL2008 protocol.  By combining minimal residual disease (MRD) status at treatment day 29 and CIMP status at diagnosis we could further separate T-ALL patients into risk groups.

    Likewise, the CIMP profile could separate relapsed BCP-ALL patients into risk groups, where the CIMP- cases had a significantly worse outcome compared to CIMP+ cases.  From these data we conclude that DNA methylation subgrouping is a promising prognostic marker in T-ALL, as well as in relapsed BCP-ALL two groups where reliable prognostic markers are currently missing. By elucidating the biology behind the different CIMP profiles, the pathogenesis of ALL will be further understood and may contribute to new treatment strategies.

  • 4.
    Borssén, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Norén-Nyström, Ulrika
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Schmiegelow, Kjeld
    Åsberg, Ann E.
    Kanerva, Jukka
    Madsen, Hans O.
    Marquart, Hanne
    Heyman, Mats
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology. Department of Paediatrics, University Hospital of Trondheim, Norway.
    DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia2016In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 7, p. 1185-1192Article in journal (Refereed)
    Abstract [en]

    Background. Despite increased knowledge about genetic aberrations in pediatric T-cell acute lymphoblastic leukemia (T-ALL), no clinically feasible treatment-stratifying marker exists at diagnosis. Instead patients are enrolled in intensive induction therapies with substantial side effects. In modern protocols, therapy response is monitored by minimal residual disease (MRD) analysis and used for postinduction risk group stratification. DNA methylation profiling is a candidate for subtype discrimination at diagnosis and we investigated its role as a prognostic marker in pediatric T-ALL. Procedure. Sixty-five diagnostic T-ALL samples from Nordic pediatric patients treated according to the Nordic Society of Pediatric Hematology and Oncology ALL 2008 (NOPHO ALL 2008) protocol were analyzed by HumMeth450K genome wide DNA methylation arrays. Methylation status was analyzed in relation to clinical data and early T-cell precursor (ETP) phenotype. Results. Two distinct CpG island methylator phenotype (CIMP) groups were identified. Patients with a CIMP-negative profile had an inferior response to treatment compared to CIMP-positive patients (3-year cumulative incidence of relapse (CIR3y) rate: 29% vs. 6%, P = 0.01). Most importantly, CIMP classification at diagnosis allowed subgrouping of high-risk T-ALL patients (MRD >= 0.1% at day 29) into two groups with significant differences in outcome (CIR3y rates: CIMP negative 50% vs. CIMP positive 12%; P = 0.02). These groups did not differ regarding ETP phenotype, but the CIMP-negative group was younger (P = 0.02) and had higher white blood cell count at diagnosis (P = 0.004) compared with the CIMP-positive group. Conclusions. CIMP classification at diagnosis in combination with MRD during induction therapy is a strong candidate for further risk classification and could confer important information in treatment decision making.

  • 5.
    Borssén, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Nordlund, J
    Haider, Z
    Landfors, M
    Larsson, P
    Forestier, E
    Heyman, M
    Hultdin, M
    Lönnerholm, G
    Syvänen, AC
    Degerman, S
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemiaManuscript (preprint) (Other academic)
  • 6.
    Borssén, Magnus
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nordlund, Jessica
    Haider, Zahra
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Larsson, Pär
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Kanerva, Jukka
    Schmiegelow, Kjeld
    Flaegstad, Trond
    Jónsson, Ólafur Gísli
    Frost, Britt-Marie
    Palle, Josefine
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Heyman, Mats
    Hultdin, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lönnerholm, Gudmar
    Degerman, Sofie
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia2018In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 10, article id 31Article in journal (Refereed)
    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.

  • 7.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Borssen, Magnus
    Umeå University, Faculty of Medicine. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Andersson, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Chranowska, Krystyna H.
    Department of Medical Genetics, Childrens Memorial Health institute, 04-730 Warsaw, Poland.
    Siwicki, Jan Konrad
    Department of Immunology, maria Sklodowska-Curie Memorial Cancer Centre and institute of Oncology, 02-781, Warsaw, Poland.
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Senescence bypass and immortalization of T cell cultures are linked to stepwise DNA methylation changesManuscript (preprint) (Other academic)
  • 8.
    Degerman, Sofie
    et al.
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Landfors, Mattias
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics. Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Siwicki, Jan Konrad
    Revie, John
    Borssen, Magnus
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Evelönn, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Medical and Clinical Genetics.
    Chrzanowska, Krystyna H.
    Ryden, Patrik
    Umeå University, Faculty of Science and Technology, Department of Mathematics and Mathematical Statistics.
    Keith, W. Nicol
    Roos, Göran
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Immortalization of T-Cells Is Accompanied by Gradual Changes in CpG Methylation Resulting in a Profile Resembling a Subset of T-Cell Leukemias2014In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, no 7, p. 606-615Article in journal (Refereed)
    Abstract [en]

    We have previously described gene expression changes during spontaneous immortalization of T-cells, thereby identifying cellular processes important for cell growth crisis escape and unlimited proliferation. Here, we analyze the same model to investigate the role of genome-wide methylation in the immortalization process at different time points pre-crisis and post-crisis using high-resolution arrays. We show that over time in culture there is an overall accumulation of methylation alterations, with preferential increased methylation close to transcription start sites (TSSs), islands, and shore regions. Methylation and gene expression alterations did not correlate for the majority of genes, but for the fraction that correlated, gain of methylation close to TSS was associated with decreased gene expression. Interestingly, the pattern of CpG site methylation observed in immortal T-cell cultures was similar to clinical T-cell acute lymphoblastic leukemia (T-ALL) samples classified as CpG island methylator phenotype positive. These sites were highly overrepresented by polycomb target genes and involved in developmental, cell adhesion, and cell signaling processes. The presence of non-random methylation events in in vitro immortalized T-cell cultures and diagnostic T-ALL samples indicates altered methylation of CpG sites with a possible role in malignant hematopoiesis.

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