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Acute lymphoblastic leukemia

Acute lymphoblastic leukemia and down syndrome: 6-mercaptopurine and methotrexate metabolites during maintenance therapy

Leukemia volume 35, pages 863–866 (2021)Cite this article

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Children with Down syndrome (DS) have a 20–40 times increased risk of developing acute lymphoblastic leukemia (ALL) [1] but the mechanism by which DS contributes to development of ALL remains unclear [2]. Moreover, inferior outcome for DS-ALL compared to non-DS ALL has been reported by most collaborative research groups [3,4,5].

Methotrexate (MTX) and 6-mercaptopurine (6MP) constitute the backbone of maintenance therapy (MT) of ALL [6]. 6MP is a purine analogue pro-drug [7] and multiple catabolic conversions are needed to convert 6MP to 6-thioguanine (6TGN), the cytotoxic metabolite incorporated in DNA (DNA-TG) [8]. Intracellularly, 6MP and some of its metabolites can also become thio-methylated thus shunted away from 6TGN formation. However, some methylated 6MP metabolites (MeMP) are strong inhibitors of purine de novo synthesis and can consequently enhance DNA-TG incorporation [9].

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Fig. 1: Dynamics in 6MP/MTX metabolites during maintenance therapy of childhood acute lymphoblastic leukemia, data from children with (DS) and without Down syndrome (non–DS).

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Acknowledgements

This study has received financial support from: The Danish Cancer Society (Grant nos: 91-048, 92-017, 93-017, 95-100-28, R19-A984, R214-A12962), The Otto Christensen Foundation, The Swedish Childhood Cancer Foundation (Grant nos. 53/91, 62/94, 72/96, 98/59), The Lundbeck Foundation (Grant no. 38/99) and The Danish Childhood Cancer Foundation. Thanks to the Nordic Society of Pediatric Hematology and Oncology for their participation in this study.

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Authors and Affiliations

  1. Department of Pediatrics and Adolescent Medicine, The Juliane Marie Centre, The University Hospital Rigshospitalet, Copenhagen, Denmark

    Anna Østergaard, Cathrine Bohnstedt, Kathrine Grell, Matilda Degn & Kjeld Schmiegelow

  2. Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands

    Anna Østergaard & Peter Hoogerbrugge

  3. Faculty of Medicine, Utrecht University, Utrecht, Netherlands

    Anna Østergaard & Peter Hoogerbrugge

  4. Section of Biostatistics, Department of Public Health, University of Copenhagen, Copenhagen, Denmark

    Kathrine Grell

  5. Department of Paediatrics, University Hospital Oslo, Oslo, Norway

    Bernward Zeller

  6. New Children’s Hospital, Helsinki University Hospital, Helsinki University, Helsinki, Finland

    Mervi Taskinen

  7. Department of Paediatrics, University Hospital Reykjavik, Reykjavik, Iceland

    Solveig Hafsteinsdottir & Helga Björgvinsdóttir

  8. Childhood Cancer Research Unit Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden

    Mats Heyman

  9. Institute of Clinical Medicine, The Faculty of Health Sciences, The University of Copenhagen, Copenhagen, Denmark

    Kjeld Schmiegelow

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  1. Anna Østergaard
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Consortia

on behalf of the Nordic Society of Paediatric Haematology and Oncology (NOPHO)

Contributions

AØ collected data, analyzed data and drafted the paper; CB designed the study, collected data and drafted the paper; KG analyzed data and drafted the paper; MD and PH drafted the paper; BZ, MT, SH, HB and MH collected data; KS is chair of the NOPHO ALL2008 protocol, designed the study, collected data and drafted the paper.

Corresponding author

Correspondence to Kjeld Schmiegelow.

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Østergaard, A., Bohnstedt, C., Grell, K. et al. Acute lymphoblastic leukemia and down syndrome: 6-mercaptopurine and methotrexate metabolites during maintenance therapy. Leukemia 35, 863–866 (2021). https://doi.org/10.1038/s41375-020-0946-2

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