Abstract

In acute myeloid leukemia (AML), novel therapies are needed to target not only the rapidly dividing AML blasts but also the distinct population of leukemia stem cells (LSCs), which have abnormal self-renewal capacity and increased chemotherapy resistance. Elucidation of the expression and function of deregulated genes in LSCs is critical to specifically target LSCs and may consequently lead to improving outcomes of AML patients. Here, we correlated long non-coding RNA (lncRNA) expression profiles obtained from two RNA-seq datasets of 375 younger (aged <60 years) 76 older (≥60 years) adults with cytogenetically normal AML with a ‘core enriched’ (CE) gene expression signature (GES) associated with LSCs. We identified a LSC-specific signature of 111 lncRNAs that correlated strongly with the CE-GES. Among the top upregulated LSC-associated lncRNAs, we identified the lncRNA DANCR. Further experiments confirmed that DANCR is upregulated in functionally validated LSC-enriched populations. DANCR knock-down in LSCs resulted in decreased stem-cell renewal and quiescence. Furthermore, we showed that targeting Dancr in vivo using a primary murine model of AML (expressing both Mll partial tandem duplication/Flt3 internal tandem duplication) prolonged the survival of mice after serial transplantation. Our data suggest that LSCs have a distinct lncRNA signature with functional relevance and therapeutic potential.

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Acknowledgements

We would like to thank Dr. David M. Lucas and Ms. Donna Bucci from the Leukemia Tissue Bank of The Ohio State University for sample support (CCC Support Grant: P30CA016058). This work is supported by the Leukemia Clinical Research Foundation (M.B.), Gabrielle’s Angels Foundation and ASH Bridge Grant (A.M.D).

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Author notes

  1. These authors contributed equally: Ramiro Garzon, Adrienne M. Dorrance

Affiliations

  1. The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA

    • Marius Bill
    • , Dimitrios Papaioannou
    • , Malith Karunasiri
    • , Jessica Kohlschmidt
    • , Felice Pepe
    • , Christopher J. Walker
    • , Allison E. Walker
    • , Zachary Brannan
    • , Aparna Pathmanathan
    • , Krzysztof Mrózek
    • , Allison LaRocco
    • , Clara D. Bloomfield
    • , Ramiro Garzon
    •  & Adrienne M. Dorrance
  2. Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, OH, USA

    • Malith Karunasiri
    • , Clara D. Bloomfield
    • , Ramiro Garzon
    •  & Adrienne M. Dorrance
  3. Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA

    • Xiaoli Zhang
  4. Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, Italy

    • Stefano Volinia

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The authors declare that they have no conflict of interest.

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Correspondence to Ramiro Garzon or Adrienne M. Dorrance.

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https://doi.org/10.1038/s41375-019-0429-5