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Acute Leukemias

miR-9 is a tumor suppressor in pediatric AML with t(8;21)

Leukemia volume 28, pages 1022–1032 (2014)Cite this article

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Abstract

MicroRNAs (miRNAs) play a pivotal role in the regulation of hematopoiesis and development of leukemia. Great interest emerged in modulating miRNA expression for therapeutic purposes. In order to identify miRNAs, which specifically suppress leukemic growth of acute myeloid leukemia (AML) with t(8;21), inv(16) or mixed lineage leukemia (MLL) rearrangement by inducing differentiation, we conducted a miRNA expression profiling in a cohort of 90 cytogenetically characterized, de novo pediatric AML cases. Four miRNAs, specifically downregulated in MLL-rearranged, t(8;21) or inv(16) AMLs, were characterized by their tumor-suppressive properties in cell lines representing those respective cytogenetic groups. Among those, forced expression of miR-9 reduced leukemic growth and induced monocytic differentiation of t(8;21) AML cell lines in vitro and in vivo. The tumor-suppressive functions of miR-9 were specifically restricted to AML cell lines and primary leukemic blasts with t(8;21). On the other hand, these functions were not evident in AML blasts from patients with MLL rearrangements. We showed that miR-9 exerts its effects through the cooperation with let-7 to repress the oncogenic LIN28B/HMGA2 axis. Thus, miR-9 is a tumor suppressor-miR which acts in a stringent cell context-dependent manner.

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Acknowledgements

The authors would like to thank J Schoening for general lab support; Drs. K Weber and B Fehse for providing plasmids. SE, FE, RJ and KH were supported by the Hannover Biomedical Research School. JEK-K, LV and AAD-vO were supported by the Children Cancer Free Foundation (KIKA, project 49). JHK is a fellow of the Emmy Noether-Programme from the German Research Foundation (DFG; KL-2374/2-1). This work was supported by grants to JHK from the DFG (KL-2374/2-1) and to JEK, CMZ and MMvdH-E from KIKA (project 49).

Author contributions

SE, KH, FE, RJ, FD, and MEK performed all in vitro and in vivo experiments and analyzed data. JEK-K, LV, AAD-vO. performed expression studies and analyzed data. SE designed experiments and wrote the manuscript. KH and JEK-K wrote the manuscript. MEK revised the manuscript. JHK designed and supervised the study, analyzed data and wrote the paper. MMvdH-E designed and supervised the study and wrote the manuscript. DR, JS, AB and VdH contributed materials and clinical data and revised the manuscript. DR, CMZ, MLdB, MF and RP supervised the study and revised the manuscript.

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Author notes

  1. S Emmrich, J E Katsman-Kuipers, J H Klusmann and M M van den Heuvel-Eibrink: These authors contributed equally to this study.

Authors and Affiliations

  1. Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany

    S Emmrich, K Henke, M E Khatib, R Jammal, F Engeland, F Dasci, D Reinhardt & J H Klusmann

  2. Pediatric Oncology/Hematology/Biochemistry, Erasmus MC/Sophia Children’s Hospital, Rotterdam, The Netherlands

    J E Katsman-Kuipers, C M Zwaan, M L den Boer, L Verboon, A A Danen-van Oorschot, M Fornerod, R Pieters & M M van den Heuvel-Eibrink

  3. Pediatric Hematology/Oncology, Charles University and University Hospital Motol, Prague, Czech Republic

    J Stary

  4. Hematology, St. Louis Hospital, Paris, France

    A Baruchel

  5. Dutch Childhood Oncology Group (DCOG), The Hague, The Netherlands

    V de Haas

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  1. S Emmrich
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Correspondence to J H Klusmann or M M van den Heuvel-Eibrink.

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Emmrich, S., Katsman-Kuipers, J., Henke, K. et al. miR-9 is a tumor suppressor in pediatric AML with t(8;21). Leukemia 28, 1022–1032 (2014). https://doi.org/10.1038/leu.2013.357

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