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Acute Leukemias

Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale

Leukemia volume 25, pages 429–439 (2011)Cite this article

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Abstract

MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is the most aggressive type of childhood leukemia. To develop more suitable treatment strategies, a firm understanding of the biology underlying this disease is of utmost importance. MLL-rearranged ALL displays a unique gene expression profile, partly explained by erroneous histone modifications. We recently showed that t(4;11)-positive infant ALL is also characterized by pronounced promoter CpG hypermethylation. In this study, we investigated whether this widespread hypermethylation also affected microRNA (miRNA) expression. We identified 11 miRNAs that were downregulated in t(4;11)-positive infant ALL as a consequence of CpG hypermethylation. Seven of these miRNAs were re-activated after exposure to the de-methylating agent Zebularine. Interestingly, five of these miRNAs are associated either with MLL or MLL fusions, and for miR-152 we found both MLL and DNA methyltransferase 1 (DNMT1) as potential targeted genes. Finally, a high degree of methylation of the miR-152 CpG island was strongly correlated with a poor clinical outcome. Our data suggests that inhibitors of methylation have a potential beyond re-expression of hypermethylated protein-coding genes in t(4;11)-positive infant ALL. In this study, we provide additional evidence that they should be tested for their efficacy in MLL-rearranged infant ALL in in vivo models.

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Acknowledgements

We wish to express gratitude to the members and participating hospitals of the INTERFANT-99 study for supporting our research by providing leukemic samples. Members of INTERFANT-99 are: Campbell M (PINDA), Felice M (Argentina), Ferster A (CLCG), Hann I and Vora A (UKCCSG), Hovi L (NOPHO), Janka-Schaub G (COALL), Li CK (Hong Kong), Mann G (BFM-A), LeBlanc T (FRALLE), Pieters R (DCOG), de Rossi G and Biondi A (AIEOP), Rubnitz J (SJCRH), Schrappe M (BFM-G), Silverman L (DFCI), Stary J (CPH), Suppiah R (ANZCHOG), Szczepanski T (PPLLSG), Valsecchi M and de Lorenzo P (CORS).This study was financially supported by grants from the Sophia Foundation for Medical Research (SSWO Grant 495, RWS/RP), the Dutch Cancer Society (EMCR 2005–2662, MLdB/RP), The Netherlands Organization for Scientific Research (NWO-Vidi Grant, MLdB) and the Pediatric Oncology Foundation Rotterdam (MLdB/RP). Furthermore, this research was supported in part by the Intramural Research Program of the NIH, National Cancer Institute and Center for Cancer Research (VEM).

Authorship contributions

DJPMS and DS performed research and wrote the manuscript; EAMLT, PS and LS performed research; RXdM provided statistical guidance; VEM reviewed the paper; RWS, MLdB and RP designed and guided research, reviewed and wrote the manuscript. All authors read and approved the final manuscript.

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Author notes

  1. D J P M Stumpel and D Schotte: These authors contributed equally to this work.

  2. M L den Boer and R W Stam: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Oncology/Hematology, Erasmus Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands

    D J P M Stumpel, D Schotte, E A M Lange-Turenhout, P Schneider, L Seslija, R X de Menezes, R Pieters, M L den Boer & R W Stam

  2. Chemical Biology Laboratory, Center for Cancer Research, National Cancer Institute at Frederick, National Institutes of Health, Frederick, MD, USA

    V E Marquez

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Stumpel, D., Schotte, D., Lange-Turenhout, E. et al. Hypermethylation of specific microRNA genes in MLL-rearranged infant acute lymphoblastic leukemia: major matters at a micro scale. Leukemia 25, 429–439 (2011). https://doi.org/10.1038/leu.2010.282

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