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Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 6, e65373- p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2013. Vol. 8, no 6, e65373- p.
National Category
Cancer and Oncology Pediatrics
Identifiers
URN: urn:nbn:se:umu:diva-79269DOI: 10.1371/journal.pone.0065373ISI: 000321099000061OAI: oai:DiVA.org:umu-79269DiVA: diva2:645310
Available from: 2013-09-04 Created: 2013-08-13 Last updated: 2017-12-06Bibliographically approved
In thesis
1. DNA methylation as a prognostic marker i acute lymphoblastic leukemia
Open this publication in new window or tab >>DNA methylation as a prognostic marker i acute lymphoblastic leukemia
2016 (English)Doctoral 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.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2016. 69 p.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1857
Keyword
DNA methylation, acute lymphoblastic leukemia, T-ALL, Relapse, Telomere length
National Category
Pediatrics Cancer and Oncology
Research subject
Pathology; Pediatrics
Identifiers
urn:nbn:se:umu:diva-127225 (URN)978-91-7601-583-4 (ISBN)
Public defence
2016-11-25, Sal B, 9t, Tandläkarhögskolan NUS, Norrlands universitetssjukhus 90185 Umeå, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2016-11-04 Created: 2016-11-03 Last updated: 2016-11-17Bibliographically approved

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