umu.sePublikationer
Ändra sökning
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf
hTERT promoter methylation and telomere length in childhood acute lymphoblastic leukemia-associations with immunophenotype and cytogenetic subgroup
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
Umeå universitet, Medicinska fakulteten, Institutionen för medicinsk biovetenskap.
Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
Visa övriga samt affilieringar
2011 (Engelska)Ingår i: Experimental Hematology, ISSN 0301-472X, E-ISSN 1873-2399, Vol. 39, nr 12, s. 1144-1151Artikel i tidskrift (Refereegranskat) 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.

Ort, förlag, år, upplaga, sidor
New York: Elsevier, 2011. Vol. 39, nr 12, s. 1144-1151
Nationell ämneskategori
Hematologi
Identifikatorer
URN: urn:nbn:se:umu:diva-50932DOI: 10.1016/j.exphem.2011.08.014ISI: 000297566500005OAI: oai:DiVA.org:umu-50932DiVA, id: diva2:473229
Tillgänglig från: 2012-01-05 Skapad: 2012-01-02 Senast uppdaterad: 2018-06-08Bibliografiskt granskad
Ingår i avhandling
1. DNA methylation as a prognostic marker i acute lymphoblastic leukemia
Öppna denna publikation i ny flik eller fönster >>DNA methylation as a prognostic marker i acute lymphoblastic leukemia
2016 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
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.

Ort, förlag, år, upplaga, sidor
Umeå: Umeå universitet, 2016. s. 69
Serie
Umeå University medical dissertations, ISSN 0346-6612 ; 1857
Nyckelord
DNA methylation, acute lymphoblastic leukemia, T-ALL, Relapse, Telomere length
Nationell ämneskategori
Pediatrik Cancer och onkologi
Forskningsämne
patologi; pediatrik
Identifikatorer
urn:nbn:se:umu:diva-127225 (URN)978-91-7601-583-4 (ISBN)
Disputation
2016-11-25, Sal B, 9t, Tandläkarhögskolan NUS, Norrlands universitetssjukhus 90185 Umeå, Umeå, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2016-11-04 Skapad: 2016-11-03 Senast uppdaterad: 2018-06-09Bibliografiskt granskad

Open Access i DiVA

Fulltext saknas i DiVA

Övriga länkar

Förlagets fulltext

Personposter BETA

Borssen, MagnusCullman, IngerNorén-Nyström, UlrikaForestier, ErikRoos, Göran

Sök vidare i DiVA

Av författaren/redaktören
Borssen, MagnusCullman, IngerNorén-Nyström, UlrikaForestier, ErikRoos, Göran
Av organisationen
Institutionen för medicinsk biovetenskapPediatrik
I samma tidskrift
Experimental Hematology
Hematologi

Sök vidare utanför DiVA

GoogleGoogle Scholar

doi
urn-nbn

Altmetricpoäng

doi
urn-nbn
Totalt: 308 träffar
RefereraExporteraLänk till posten
Permanent länk

Direktlänk
Referera
Referensformat
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Annat format
Fler format
Språk
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Annat språk
Fler språk
Utmatningsformat
  • html
  • text
  • asciidoc
  • rtf