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Acute Leukemias

Hsa-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals independent of p53

Leukemia volume 24, pages 89–96 (2010)Cite this article

Abstract

MicroRNAs (miRNAs) regulate the expression of multiple proteins in a dose-dependent manner. We hypothesized that increased expression of miRNAs encoded on chromosome 21 (chr 21) contribute to the leukemogenic function of trisomy 21. The levels of chr 21 miRNAs were quantified by qRT–PCR in four types of childhood acute lymphoblastic leukemia (ALL) characterized by either numerical (trisomy or tetrasomy) or structural abnormalities of chr 21. Suprisingly, high expression of the hsa-mir-125b-2 cluster, consisting of three miRNAs, was identified in leukemias with the structural ETV6/RUNX1 abnormality and not in ALLs with trisomy 21. Manipulation of ETV6/RUNX1 expression and chromatin immunoprecipitation studies showed that the high expression of the miRNA cluster is an event independent of the ETV6/RUNX1 fusion protein. Overexpression of hsa-mir-125b-2 conferred a survival advantage to Ba/F3 cells after IL-3 withdrawal or a broad spectrum of apoptotic stimuli through inhibition of caspase 3 activation. Conversely, knockdown of the endogenous miR-125b in the ETV6/RUNX1 leukemia cell line REH increased apoptosis after Doxorubicin and Staurosporine treatments. P53 protein levels were not altered by miR-125b. Together, these results suggest that the expression of hsa-mir-125b-2 in ETV6/RUNX1 ALL provides survival advantage to growth inhibitory signals in a p53-independent manner.

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Acknowledgements

We thank J Crispino, G Lavi and Y Sidi for providing reagents; M Oren for fruitful discussions and provision of reagents; the Department of Pediatric Hematology and Oncology, Dr von Haunersches Kinderspital, Munich, Germany, for providing clinical samples; members of SI and AB laboratories for helpful discussions and, in particular, P Landgraf for his excellent criticism and advice. SI, NG, VB and AB designed experiments. NG, VB, YL, MM, OW, MZ, JT, LE, NS, AN designed and performed experiments. LH analyzed data. NG, VB, AB, SI wrote the paper. This work was supported by National Institute of Health R01 CA120772-01A2 (SI), German Israeli Foundation (SI & AB), The Wolfson Foundation (SI, NS), Israel Science Foundation Morasha (SI), Children with Leukaemia UK (SI), Leukemia Research Fund UK (OW and MM), Curtis Katz (SI), MSM0021620813 and MZO00064203 (JT and MZ), Jewish National Fund, UK (SI), Claudine Galli Foundation (NG), Converging Technologies program (LH), Elterninitiative Kinderkrebsklinik Duesseldorf (AB). The study has been performed as partial fulfillment of the requirements for PhD degree of Nir Gefen and Libi Hertzberg, Sackler School of Medicine, Tel Aviv University.

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Author notes

  1. N Gefen and V Binder: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Pediatric Hemato-Oncology, Section of Functional Genomics and Leukemia Research, Sheba Medical Center, Tel-Hashomer, Israel

    N Gefen, V Binder, L Hertzberg & S Izraeli

  2. Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    N Gefen, L Hertzberg & S Izraeli

  3. Department of Pediatric Hematology, Oncology and Immunology, Heinrich Heine University, Duesseldorf, Germany

    V Binder, Y Linka, A Novosel & A Borkhardt

  4. Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and University Hospital Motol, Childhood Leukemia Investigation Prague, Prague, Czech Republic

    M Zaliova & J Trka

  5. Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    L Edry & N Shomron

  6. Institute of Child Health, University College London, London, UK

    M Morrow & O Williams

  7. Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, Israel

    L Hertzberg

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Gefen, N., Binder, V., Zaliova, M. et al. Hsa-mir-125b-2 is highly expressed in childhood ETV6/RUNX1 (TEL/AML1) leukemias and confers survival advantage to growth inhibitory signals independent of p53. Leukemia 24, 89–96 (2010). https://doi.org/10.1038/leu.2009.208

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