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DNA Methylation Adds Prognostic Value to Minimal Residual Disease Status in Pediatric T-Cell Acute Lymphoblastic Leukemia
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
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2016 (English)In: Pediatric Blood & Cancer, ISSN 1545-5009, E-ISSN 1545-5017, Vol. 63, no 7, p. 1185-1192Article 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.

Place, publisher, year, edition, pages
2016. Vol. 63, no 7, p. 1185-1192
Keywords [en]
childhood leukemia, DNA methylation, MRD, prognosis, T-ALL, WBC
National Category
Cancer and Oncology Hematology Pediatrics
Identifiers
URN: urn:nbn:se:umu:diva-124837DOI: 10.1002/pbc.25958ISI: 000380105400008PubMedID: 26928953OAI: oai:DiVA.org:umu-124837DiVA, id: diva2:1010366
Available from: 2016-10-03 Created: 2016-08-26 Last updated: 2019-05-10Bibliographically 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. p. 69
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1857
Keywords
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: 2018-06-09Bibliographically approved
2. DNA methylation signatures in precursor lymphoid neoplasms: with focus on clinical implications &  the biology behind
Open this publication in new window or tab >>DNA methylation signatures in precursor lymphoid neoplasms: with focus on clinical implications &  the biology behind
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Precursor lymphoid neoplasms, namely acute lymphoblastic leukemias (ALL) and lymphoblastic lymphomas (LBL), are characterized by an aggressive proliferation of malignant progenitor B- or T-cells. To improve risk classification at diagnosis, better prognostic and treatment stratifying biomarkers are needed. Altered DNA methylation pattern is a hallmark of neoplastic transformation, and has been employed as a molecular prognostic and predictive marker in various cancers, including hematological malignancies. Our research group previously identified a CpG island methylator phenotype (CIMP) panel that classified pediatric T-ALL patients into prognostic subgroups.

The aim of this thesis was to evaluate distinct DNA methylation signatures in precursor lymphoid neoplasms, and to validate the prognostic value of CIMP classification in separate patient cohorts. Additionally, the biological mechanisms underlying the distinct CIMP methylation signatures in these malignancies were investigated.

The prognostic relevance of CIMP classification was validated in an independent Nordic cohort of pediatric T-ALL patients. Combination of CIMP status with minimal residual disease (MRD) status, could further dissect the high-risk MRD positive T-ALL patients into two CIMP subgroups with significantly distinct outcomes. Furthermore, CIMP classification at diagnosis was shown to predict overall survival in relapsed BCP-ALL patients. CIMP methylation signatures were also identified in T-LBL patients, indicating a broader relevance of CIMP based classification in lymphoid malignancies. Investigating the biology behind CIMP methylation signatures showed the association of CIMP status with the proliferative history of the leukemic cells. A differential transcriptomic analysis revealed a correlation of CIMP subgroups with known T-ALL drivers, as well as with novel genes in T-ALL biology. Finally, we identified distinct DNA methylation patterns and genetic aberrations in T-ALL and T-LBL that might contribute to the different clinical presentation of these two diseases. In conclusion, we validated the prognostic significance of CIMP methylation signature in precursor lymphoid malignancies and identified transcriptomic profiles that associated with the subgroups. DNA methylation is a strong candidate for further risk classification in lymphoid neoplasms and our findings can contribute to the identification of new potential targets for treatment.

Place, publisher, year, edition, pages
Umeå: Umeå University, 2019. p. 82
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 2015
Keywords
Acute Lymphoblastic Leukemia, Lymphoma, T-ALL, BCP-ALL, T-LBL, DNA methylation, CIMP, Prognosis, TAL1, HOX.
National Category
Cancer and Oncology Hematology Pediatrics Biochemistry and Molecular Biology Genetics
Identifiers
urn:nbn:se:umu:diva-156642 (URN)978-91-7855-023-4 (ISBN)
Public defence
2019-03-15, Hörsal Betula, Norrlands universitetssjukhus, 90185, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2019-02-22 Created: 2019-02-20 Last updated: 2019-03-14Bibliographically approved

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Borssén, MagnusHaider, ZahraLandfors, MattiasNorén-Nyström, UlrikaHultdin, MagnusRoos, GöranForestier, ErikDegerman, Sofie

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