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Acute Leukemias

Acute myeloid leukemia with translocation (8;16)(p11;p13) and MYST3-CREBBP rearrangement harbors a distinctive microRNA signature targeting RET proto-oncogene

Leukemia volume 27, pages 595–603 (2013)Cite this article

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Abstract

Acute myeloid leukemia (AML) with t(8;16)(p11;p13) (t(8;16) AML) has unique clinico-biological characteristics, but its microRNA pattern is unknown. We analyzed 670 microRNAs in seven patients with t(8;16) AML and 113 with other AML subtypes. Hierarchical cluster analysis showed that all t(8;16) AML patients grouped in an independent cluster. Supervised analysis revealed a distinctive signature of 94-microRNAs, most of which were downregulated, including miR-21 and cluster miR-17–92. The mRNA expression analysis of two known transcription factors of these microRNAs (STAT3 and c-Myc, respectively) showed significant downregulation of STAT3 (P=0.04). A bioinformatic analysis showed that 29 of the downregulated microRNAs might be regulated by methylation; we treated a t(8;16) AML sample with 5-aza-2′-deoxycytidine (5-AZA-dC) and trichostatin A and found that 27 microRNAs were re-expressed after treatment. However, there was no difference in methylation status between t(8;16) and other AML subtypes, either overall or in the microRNA promoter. Cross-correlation of mRNA and microRNA expression identified RET as a potential target of several microRNAs. A Renilla-luciferase assay and flow cytometry after transfection with pre-microRNAs confirmed that RET is regulated by miR-218, miR-128, miR-27b, miR-15a and miR-195. In conclusion, t(8;16) AML harbors a specific microRNA signature that is partially epigenetically regulated and targets RET proto-oncogene.

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Acknowledgements

We thank Dr Francesco Lo Coco and Dr Tiziana Ottone (Hospital Tor Vergata, Rome), Dr David Grimwade and Dr Adam Ivey (Guy’s Hospital, London), and Dr Olga Salamero (Hospital Vall d’Hebron, Barcelona) for kindly providing us with three additional cases of AML associated to translocation t(8;16). This work was supported by grants from Fondo de Investigaciones Sanitarias/Instituto de Salud Carlos III PI080158, FIS-PI0900547 and N-2004-FS041085, and RETICS RD06/0020/0004. Marina Díaz-Beyá is supported by a ‘Premi Fi de Residència Emili Letang’ of the Hospital Clínic de Barcelona and Tania Díaz is an FI fellow supported by AGAUR, Generalitat de Catalunya and Fondo Social Europeo. Gerardo Ferrer is the recipient of a grant from ‘Instituto de Salud Carlos III’ (PFIS).

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  1. M Díaz-Beyá and A Navarro: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Hospital Clínic, University of Barcelona, Barcelona, Spain

    M Díaz-Beyá, G Ferrer, M Pratcorona & J Esteve

  2. Molecular Oncology and Embryology Laboratory, Human Anatomy Unit, School of Medicine, University of Barcelona, IDIBAPS, Barcelona, Spain

    A Navarro, T Díaz & M Monzo

  3. Genetic Variation and Cancer Group, Institute of Predictive and Personalized Medicine of Cancer, Badalona, Spain

    B Gel

  4. Department of Pediatric Hematology Department, Hospital Sant Joan de Déu de Barcelona, Esplugues de Llobregat, Spain

    M Camós & M Torrebadell

  5. Hematopathology Unit, Hospital Clínic Barcelona, University of Barcelona, Barcelona, Spain

    M Rozman & D Colomer

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Correspondence to J Esteve.

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This research was presented in part at ASH 2010 meeting as an oral presentation.

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Díaz-Beyá, M., Navarro, A., Ferrer, G. et al. Acute myeloid leukemia with translocation (8;16)(p11;p13) and MYST3-CREBBP rearrangement harbors a distinctive microRNA signature targeting RET proto-oncogene. Leukemia 27, 595–603 (2013). https://doi.org/10.1038/leu.2012.278

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