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Acute Leukemias

Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia

Leukemia volume 26, pages 682–692 (2012)Cite this article

Abstract

MLL-rearranged infant acute lymphoblastic leukemia (ALL) is an aggressive type of leukemia characterized by a unique gene-expression profile. We uncovered that the activation of particular (proto-onco)genes is mediated by promoter hypomethylation. In search for therapeutic agents capable of targeting these potential cancer-promoting genes, we applied connectivity mapping on a gene expression signature based on the genes most significantly hypomethylated in t(4;11)-positive infant ALL as compared with healthy bone marrows. This analysis revealed histone deacetylase (HDAC) inhibitors as suitable candidates to reverse the unfavorable gene signature. We show that HDAC inhibitors effectively induce leukemic cell death in t(4;11)-positive primary infant ALL cells, accompanied by downregulation of MYC, SET, RUNX1, RAN as well as the MLL–AF4 fusion product. Furthermore, DNA methylation was restored after HDAC inhibitor exposure. Our data underlines the essential role for epigenetic de-regulation in MLL-rearranged ALL. Furthermore, we show, for the first time, that connectivity mapping can indirectly be applied on DNA methylation patterns, providing a rationale for HDAC inhibition in t(4;11)-positive leukemias. Given the presented potential of HDAC inhibitors to target important proto-oncogenes including the leukemia-specific MLL fusion in vitro, these agents should urgently be tested in in vivo models and subsequent clinical trials.

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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), and Valsecchi M and de Lorenzo P (CORS). In addition, we thank Rolinda Stigter and Henk Westerhof from the Diagnostic Laboratory in the Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands, for their assistance in providing normal pediatric bone marrow samples. This study was financially supported by grants from the Sophia Foundation for Medical Research (SSWO grants 495 and 600), and RWS was financially supported by the Dutch Cancer Society (EMCR 2005–2662). The institutions financially supporting this study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Author contributions

DJPMS designed and performed research and wrote the paper. PS, LS and HO performed research. OW reviewed the paper. RWS and RP designed and guided research, and wrote the paper.

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Authors and Affiliations

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

    D J P M Stumpel, P Schneider, L Seslija, R Pieters & R W Stam

  2. Molecular Haematology and Cancer Biology Unit, University College London Institute of Child Health and Great Ormond Street Hospital for Children, London, UK

    H Osaki & O Williams

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Correspondence to R W Stam.

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Stumpel, D., Schneider, P., Seslija, L. et al. Connectivity mapping identifies HDAC inhibitors for the treatment of t(4;11)-positive infant acute lymphoblastic leukemia. Leukemia 26, 682–692 (2012). https://doi.org/10.1038/leu.2011.278

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