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DNA methylation pattern is altered in childhood T-cell acute lymphoblastic leukemia patients as compared with normal thymic subsets: insights into CpG island methylator phenotype in T-ALL

Leukemia volume 26, pages 367–371 (2012)Cite this article

The therapy success rate for T-cell acute lymphoblastic leukemia (T-ALL) is significantly lower than that for precursor B-cell acute lymphoblastic leukemia. Relapse of the disease and therapy-related toxicity are the most common causes of unfavorable outcome. Therefore, accurate stratification is essential to avoid both undertreatment and overtreatment of patients. T-cell receptor gene-based minimal residual disease (MRD) quantification is so far the only most clinically relevant prognostic factor in T-ALL.1, 2 However, as it is laborious and time consuming, there is an urgent need for identification of novel prognostic factors in T-ALL.

Hypermethylation of CpG islands is a recognized mechanism of inactivation of tumor suppressor genes, associated with neoplastic transformation. Different cancer types are characterized by unique methylation patterns, which could be useful for diagnostic and prognostic purposes.3 However, methylation pattern in T-ALL has only been analyzed by one group so far4 and their results need to be verified in larger cohorts of patients. One of the currently most intriguing questions arising in epigenetics concerns the existence of a CpG island methylator phenotype (CIMP).5 As proposed by Toyota et al., patients might be classified into two distinct groups, presenting with different clinical, histological and molecular characteristics, based on the number of hypermethylated genes: CIMP+, with many hypermethylated genes, and CIMP−, with a low number of hypermethylated genes. To date, there has only been one study addressing the CIMP phenomenon in T-ALL.4 Here, we report for the first time the CpG islands methylation status of 20 genes determined in T-ALL pediatric patients, healthy children and in normal thymic cells. In our T-ALL cohort we analyzed the methylation status of 15 genes reported by others to be hypermethylated in T-ALL4 and 5 additional genes, suspected or newly identified factors in tumorigenesis of this disease. This was to determine if the methylation pattern of these genes is characteristic to T-ALL or related to developmental stages of normal thymocytes. In addition, we analyzed the obtained results in regard to current findings on CIMP in T-ALL and in other tumors.6

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Acknowledgements

This work was supported by grants from the Polish Ministry of Science and Higher Education (NN407531438 to TS, NN407311839 to MD and NN407145338 to MW). MDK was additionally supported by the European Molecular Biology Organization (EMBO) short-term fellowship no. 241-09.

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Authors and Affiliations

  1. Department of Molecular and Clinical Genetics, Institute of Human Genetics, Polish Academy of Sciences, Poznań, Poland

    M D Kraszewska, M Dawidowska, M Kosmalska, M Szczepaniak & M Witt

  2. Department of Immunology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands

    N S D Larmonie & A W Langerak

  3. Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland

    Ł Sędek & T Szczepański

  4. Department of Internal Diseases, Diabetology and Nephrology, Medical University of Silesia, Zabrze, Poland

    W Grzeszczak

  5. International Institute of Molecular and Cell Biology, Warsaw, Poland

    M Szczepaniak & M Witt

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  1. M D Kraszewska
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  2. M Dawidowska
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members of the Polish Pediatric Leukemia Lymphoma Study Group (PPLLSG)

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Correspondence to M D Kraszewska.

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Supplementary Information accompanies the paper on the Leukemia website

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Appendix

Appendix

The PPLLSG investigators include Iwona Malinowska, Michał Matysiak (Department of Pediatric Hematology and Oncology, Medical University of Warsaw), Jerzy R Kowalczyk, Monika Lejman (Department of Pediatric Hematology and Oncology, Medical University, Lublin) Katarzyna Derwich, Jacek Wachowiak (Department of Pediatric Hematology, Oncology and Transplantology, University of Medical Sciences, Poznań), Joanna Trelinska, Wojciech Młynarski (Department of Pediatric Oncology, Hematology and Diabetology, Medical University, Łódź), Grażyna Sobol (Department of Pediatrics, Medical University of Silesia, Katowice) Katarzyna Muszyńska-Roslan, Maryna Krawczuk-Rybak (Department of Pediatric Oncology, Medical University, Bialystok) Wanda Badowska (Regional Specialistic Pediatric Hospital, Olsztyn), Maciej Niedźwiecki, Anna Balcerska (Department of Pediatric Hematology, Oncology and Endocrinology, Medical University, Gdańsk) Maria Wieczorek (Chorzów Center of Pediatrics and Oncology, Chorzów), Tomasz Ociepa and Tomasz Urasiński (Department of Pediatrics, Hematology and Oncology, Pomeranian Medical University, Szczecin).

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Kraszewska, M., Dawidowska, M., Larmonie, N. et al. DNA methylation pattern is altered in childhood T-cell acute lymphoblastic leukemia patients as compared with normal thymic subsets: insights into CpG island methylator phenotype in T-ALL. Leukemia 26, 367–371 (2012). https://doi.org/10.1038/leu.2011.208

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