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DNA methylation holds prognostic information in relapsed precursor B-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.
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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. Vol. 10, article id 31
Keywords [en]
DNA methylation, BCP-ALL, prognosis, CIMP, relapse, risk stratification
National Category
Hematology
Identifiers
URN: urn:nbn:se:umu:diva-146216DOI: 10.1186/s13148-018-0466-3ISI: 000427080200001PubMedID: 29515676OAI: oai:DiVA.org:umu-146216DiVA, id: diva2:1204518
Available from: 2018-05-08 Created: 2018-05-08 Last updated: 2019-02-20Bibliographically approved
In thesis
1. 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)
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Available from: 2019-02-22 Created: 2019-02-20 Last updated: 2019-03-14Bibliographically approved

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Borssén, MagnusHaider, ZahraLandfors, MattiasLarsson, PärForestier, ErikHultdin, MagnusDegerman, Sofie

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