Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Acute myeloid leukemia

Expression and functional relevance of long non-coding RNAs in acute myeloid leukemia stem cells

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Döhner H, Estey E, Grimwade D, Appelbaum FR, Büchner T, Burnett AK, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115:453–74.

    Article  Google Scholar 

  2. 2.

    Mrózek K, Heerema NA, Bloomfield CD. Cytogenetics in acute leukemia. Blood Rev. 2004;18:115–36.

    Article  Google Scholar 

  3. 3.

    Mrózek K, Marcucci G, Paschka P, Whitman SP, Bloomfield CD. Clinical relevance of mutations and gene-expression changes in adult acute myeloid leukemia with normal cytogenetics: are we ready for a prognostically prioritized molecular classification? Blood. 2007;109:431–48.

    Article  Google Scholar 

  4. 4.

    Döhner H, Weisdorf DJ, Bloomfield CD. Acute myeloid leukemia. N Engl J Med. 2015;373:1136–52.

    Article  Google Scholar 

  5. 5.

    Metzeler KH, Maharry K, Kohlschmidt J, Volinia S, Mrózek K, Becker H, et al. A stem cell-like gene expression signature associates with inferior outcomes and a distinct microRNA expression profile in adults with primary cytogenetically normal acute myeloid leukemia. Leukemia. 2013;27:2023–31.

    CAS  Article  Google Scholar 

  6. 6.

    Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P, et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med. 2011;17:1086–93.

    CAS  Article  Google Scholar 

  7. 7.

    Dick JE. Stem cell concepts renew cancer research. Blood. 2008;112:4793–807.

    CAS  Article  Google Scholar 

  8. 8.

    Dorrance AM, Neviani P, Ferenchak GJ, Huang X, Nicolet D, Maharry KS, et al. Targeting leukemia stem cells in vivo with antagomiR-126 nanoparticles in acute myeloid leukemia. Leukemia. 2015;29:2143–53.

    CAS  Article  Google Scholar 

  9. 9.

    Ng SW, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016;540:433–7.

    CAS  Article  Google Scholar 

  10. 10.

    Sagar J, Chaib B, Sales K, Winslet M, Seifalian A. Role of stem cells in cancer therapy and cancer stem cells: a review. Cancer Cell Int. 2007;7:9.

    Article  Google Scholar 

  11. 11.

    Sarry J-E, Murphy K, Perry R, Sanchez PV, Secreto A, Keefer C, et al. Human acute myelogenous leukemia stem cells are rare and heterogeneous when assayed in NOD/SCID/IL2Rγc-deficient mice. J Clin Invest. 2011;121:384–95.

    CAS  Article  Google Scholar 

  12. 12.

    Heidel FH, Mar BG, Armstrong SA. Self-renewal related signaling in myeloid leukemia stem cells. Int J Hematol. 2011;94:109–17.

    Article  Google Scholar 

  13. 13.

    Jentzsch M, Bill M, Nicolet D, Leiblein S, Schubert K, Pless M, et al. Prognostic impact of the CD34+/CD38− cell burden in patients with acute myeloid leukemia receiving allogeneic stem cell transplantation. Am J Hematol. 2017;92:388–96.

    CAS  Article  Google Scholar 

  14. 14.

    Guan Y, Gerhard B, Hogge DE. Detection, isolation, and stimulation of quiescent primitive leukemic progenitor cells from patients with acute myeloid leukemia (AML). Blood. 2003;101:3142–9.

    CAS  Article  Google Scholar 

  15. 15.

    Misaghian N, Ligresti G, Steelman LS, Bertrand FE, Bäsecke J, Libra M, et al. Targeting the leukemic stem cell: the Holy Grail of leukemia therapy. Leukemia. 2009;23:25–42.

    CAS  Article  Google Scholar 

  16. 16.

    Guzman ML, Rossi RM, Neelakantan S, Li X, Corbett CA, Hassane DC, et al. An orally bioavailable parthenolide analog selectively eradicates acute myelogenous leukemia stem and progenitor cells. Blood. 2007;110:4427–35.

    CAS  Article  Google Scholar 

  17. 17.

    Garzon R, Volinia S, Papaioannou D, Nicolet D, Kohlschmidt J, Yan PS, et al. Expression and prognostic impact of lncRNAs in acute myeloid leukemia. Proc Natl Acad Sci USA. 2014;111:18679–84.

    CAS  Article  Google Scholar 

  18. 18.

    Rinn JL, Chang HY. Genome regulation by long noncoding RNAs. Annu Rev Biochem. 2012;81:145–66.

    CAS  Article  Google Scholar 

  19. 19.

    Kapranov P, Cheng J, Dike S, Nix DA, Duttagupta R, Willingham AT, et al. RNA maps reveal new RNA classes and a possible function for pervasive transcription. Science. 2007;316:1484–8.

    CAS  Article  Google Scholar 

  20. 20.

    Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012;22:1775–89.

    CAS  Article  Google Scholar 

  21. 21.

    Hung C-L, Wang L-Y, Yu Y-L, Chen HW, Srivastava S, Petrovics G, et al. A long noncoding RNA connects c-Myc to tumor metabolism. Proc Natl Acad Sci USA. 2014;111:18697–702.

    CAS  Article  Google Scholar 

  22. 22.

    Ji P, Diederichs S, Wang W, Böing S, Metzger R, Schneider PM, et al. MALAT-1, a novel noncoding RNA, and thymosin β4 predict metastasis and survival in early-stage non-small cell lung cancer. Oncogene. 2003;22:8031–41.

    Article  Google Scholar 

  23. 23.

    Yuan S-X, Wang J, Yang F, Tao QF, Zhang J, Wang LL, et al. Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1. Hepatology. 2016;63:499–511.

    CAS  Article  Google Scholar 

  24. 24.

    Papaioannou D, Nicolet D, Volinia S, Mrózek K, Yan P, Bundschuh R, et al. Prognostic and biologic significance of long non-coding RNA profiling in younger adults with cytogenetically normal acute myeloid leukemia. Haematologica. 2017;102:1391–400.

    CAS  Article  Google Scholar 

  25. 25.

    Luo M, Jeong M, Sun D, Park HJ, Rodriguez BA, Xia Z, et al. Long non-coding RNAs control hematopoietic stem cell function. Cell Stem Cell. 2015;16:426–38.

    CAS  Article  Google Scholar 

  26. 26.

    Schwarzer A, Emmrich S, Schmidt F, Beck D, Ng M, Reimer C, et al. The non-coding RNA landscape of human hematopoiesis and leukemia. Nat Commun. 2017;8:218.

    Article  Google Scholar 

  27. 27.

    Kretz M, Webster DE, Flockhart RJ, Lee CS, Zehnder A, Lopez-Pajares V, et al. Suppression of progenitor differentiation requires the long noncoding RNA ANCR. Genes Dev. 2012;26:338–43.

    CAS  Article  Google Scholar 

  28. 28.

    Lu Q-C, Rui Z-H, Guo Z-L, Xie W, Shan S, Ren T. LncRNA-DANCR contributes to lung adenocarcinoma progression by sponging miR-496 to modulate mTOR expression. J Cell Mol Med. 2018;22:1527–37.

    CAS  Article  Google Scholar 

  29. 29.

    Jiang N, Wang X, Xie X, Liao Y, Liu N, Liu J, et al. lncRNA DANCR promotes tumor progression and cancer stemness features in osteosarcoma by upregulating AXL via miR-33a-5p inhibition. Cancer Lett. 2017;405:46–55.

    CAS  Article  Google Scholar 

  30. 30.

    Huang X, Schwind S, Yu B, Santhanam R, Wang H, Hoellerbauer P, et al. Targeted delivery of microRNA-29b by transferrin-conjugated anionic lipopolyplex nanoparticles: a novel therapeutic strategy in acute myeloid leukemia. Clin Cancer Res. 2013;19:2355–67.

  31. 31.

    Huang X, Schwind S, Santhanam R, Santhanam R, Wang H, Hoellerbauer P, et al. Targeting the RAS/MAPK pathway with miR-181a in acute myeloid leukemia. Oncotarget. 2016;7:59273–86.

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Harrow J, Frankish A, Gonzalez JM, Tapanari E, Diekhans M, Kokocinski F, et al. GENCODE: the reference human genome annotation for The ENCODE Project. Genome Res. 2012;22:1760–74.

    CAS  Article  Google Scholar 

  33. 33.

    Raffel S, Falcone M, Kneisel N, Hansson J, Wang W, Lutz C, et al. BCAT1 restricts αKG levels in AML stem cells leading to IDHmut-like DNA hypermethylation. Nature. 2017;551:384–8.

    CAS  Article  Google Scholar 

  34. 34.

    Samudio I, Harmancey R, Fiegl M, Kantarjian H, Konopleva M, Korchin B, et al. Pharmacologic inhibition of fatty acid oxidation sensitizes human leukemia cells to apoptosis induction. J Clin Invest. 2010;120:142–56.

    CAS  Article  Google Scholar 

  35. 35.

    Lechman ER, Gentner B, Ng SWK, Schoof EM, van Galen P, Kennedy JA, et al. miR-126 regulates distinct self-renewal outcomes in normal and malignant hematopoietic stem cells. Cancer Cell. 2016;29:214–28.

    CAS  Article  Google Scholar 

  36. 36.

    Zorko NA, Bernot KM, Whitman SP, Siebenaler RF, Ahmed EH, Marcucci GG, et al. Mll partial tandem duplication and Flt3 internal tandem duplication in a double knock-in mouse recapitulates features of counterpart human acute myeloid leukemias. Blood. 2012;120:1130–6.

    CAS  Article  Google Scholar 

  37. 37.

    Papaioannou D, Shen C, Nicolet D, McNeil B, Bill M, Karunasiri M, et al. Prognostic and biological significance of the proangiogenic factor EGFL7 in acute myeloid leukemia. Proc Natl Acad Sci USA. 2017;114:E4641–7.

    CAS  Article  Google Scholar 

  38. 38.

    Hu Y, Smyth GK. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods. 2008;347:70–78.

    Article  Google Scholar 

  39. 39.

    Breschi A, Gingeras TR, Guigó R. Comparative transcriptomics in human and mouse. Nat Rev Genet. 2017;18:425–40.

    CAS  Article  Google Scholar 

  40. 40.

    Zhou D, Teng F, Verhaak RGW, Su Z, Zhang Y, Brown M, et al. Integrative genomic analyses reveal clinically relevant long non-coding RNA in human cancer. Nat Struct Mol Biol. 2013;20:908–13.

    Article  Google Scholar 

  41. 41.

    Kopp F, Mendell JT. Functional classification and experimental dissection of long noncoding RNAs. Cell. 2018;172:393–407.

    CAS  Article  Google Scholar 

  42. 42.

    St. Laurent G, Wahlestedt C, Kapranov P. The landscape of long noncoding RNA classification. Trends Genet. 2015;31:239–51.

    Article  Google Scholar 

Download references

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).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Ramiro Garzon or Adrienne M. Dorrance.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bill, M., Papaioannou, D., Karunasiri, M. et al. Expression and functional relevance of long non-coding RNAs in acute myeloid leukemia stem cells. Leukemia 33, 2169–2182 (2019). https://doi.org/10.1038/s41375-019-0429-5

Download citation

Further reading

Search

Quick links