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DNA methylation as a prognostic marker i acute lymphoblastic leukemia
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
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 [en]
DNA methylation, acute lymphoblastic leukemia, T-ALL, Relapse, Telomere length
National Category
Pediatrics Cancer and Oncology
Research subject
Pathology; Pediatrics
Identifiers
URN: urn:nbn:se:umu:diva-127225ISBN: 978-91-7601-583-4OAI: oai:DiVA.org:umu-127225DiVA: diva2:1044453
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
List of papers
1. hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia-associations with immunophenotype and cytogenetic subgroup
Open this publication in new window or tab >>hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia-associations with immunophenotype and cytogenetic subgroup
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2011 (English)In: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, no 12, 1144-1151 p.Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
New York: Elsevier, 2011
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-50932 (URN)10.1016/j.exphem.2011.08.014 (DOI)000297566500005 ()
Available from: 2012-01-05 Created: 2012-01-02 Last updated: 2016-11-03Bibliographically approved
2. Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia
Open this publication in new window or tab >>Promoter DNA methylation pattern identifies prognostic subgroups in childhood T-cell acute lymphoblastic leukemia
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2013 (English)In: PLoS ONE, 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.

National Category
Cancer and Oncology Pediatrics
Identifiers
urn:nbn:se:umu:diva-79269 (URN)10.1371/journal.pone.0065373 (DOI)000321099000061 ()
Available from: 2013-09-04 Created: 2013-08-13 Last updated: 2016-11-03Bibliographically approved
3. DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia
Open this publication in new window or tab >>DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia
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2016 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 7, 1185-1192 p.Article in journal (Refereed) Published
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.

Keyword
childhood leukemia, DNA methylation, MRD, prognosis, T-ALL, WBC
National Category
Cancer and Oncology Hematology Pediatrics
Identifiers
urn:nbn:se:umu:diva-124837 (URN)10.1002/pbc.25958 (DOI)000380105400008 ()26928953 (PubMedID)
Available from: 2016-10-03 Created: 2016-08-26 Last updated: 2016-11-03Bibliographically approved
4. DNA methylation holds prognostic information in relapsed precursor B-cell acute lymphoblastic leukemia
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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(English)Manuscript (preprint) (Other academic)
National Category
Medical Bioscience
Identifiers
urn:nbn:se:umu:diva-127226 (URN)
Available from: 2016-11-03 Created: 2016-11-03 Last updated: 2016-11-03

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