lncRNA requirements for mouse acute myeloid leukemia and normal differentiation

  1. M Joaquina Delás
  2. Leah R Sabin
  3. Egor Dolzhenko
  4. Simon RV Knott
  5. Ester Munera Maravilla
  6. Benjamin T Jackson
  7. Sophia A Wild
  8. Tatjana Kovacevic
  9. Eva Maria Stork
  10. Meng Zhou
  11. Nicolas Erard
  12. Emily Lee
  13. David R Kelley
  14. Mareike Roth
  15. Inês AM Barbosa
  16. Johannes Zuber
  17. John L Rinn
  18. Andrew D Smith  Is a corresponding author
  19. Gregory J Hannon  Is a corresponding author
  1. Cold Spring Harbor Laboratory, United States
  2. University of Southern California, United States
  3. University of Cambridge, United Kingdom
  4. Watson School of Biological Sciences, United States
  5. Harvard University, United States
  6. Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Austria
  7. Cold Spring Harbor Laboratory, United Kingdom

Abstract

A substantial fraction of the genome is transcribed in a cell type-specific manner, producing long non-coding RNAs (lncRNAs), rather than protein-coding transcripts. Here we systematically characterize transcriptional dynamics during hematopoiesis and in hematological malignancies. Our analysis of annotated and de novo assembled lncRNAs showed many are regulated during differentiation and mis-regulated in disease. We assessed lncRNA function via an in vivo RNAi screen in a model of acute myeloid leukemia. This identified several lncRNAs essential for leukemia maintenance, and found that a number act by promoting leukemia stem cell signatures. Leukemia blasts show a myeloid differentiation phenotype when these lncRNAs were depleted, and our data indicates that this effect is mediated via effects on the c-MYC oncogene. Bone marrow reconstitutions showed that a lncRNA expressed across all progenitors was required for the myeloid lineage, whereas the other leukemia-induced lncRNAs were dispensable in the normal setting.

Data availability

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. M Joaquina Delás

    Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9727-9068
  2. Leah R Sabin

    Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Egor Dolzhenko

    Molecular and Computational Biology, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Simon RV Knott

    Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Ester Munera Maravilla

    Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Benjamin T Jackson

    Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  7. Sophia A Wild

    Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Tatjana Kovacevic

    Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Eva Maria Stork

    Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  10. Meng Zhou

    Molecular and Computational Biology, University of Southern California, Los Angeles, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Nicolas Erard

    Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  12. Emily Lee

    Cold Spring Harbor Laboratory, Watson School of Biological Sciences, Cold Spring Harbor, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. David R Kelley

    Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Mareike Roth

    Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  15. Inês AM Barbosa

    Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
  16. Johannes Zuber

    Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8810-6835
  17. John L Rinn

    Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Andrew D Smith

    Molecular and Computational Biology, University of Southern California, Los Angeles, United States
    For correspondence
    andrewds@usc.edu
    Competing interests
    The authors declare that no competing interests exist.
  19. Gregory J Hannon

    Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, United Kingdom
    For correspondence
    greg.hannon@cruk.cam.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4021-3898

Funding

Cancer Research UK

  • Gregory J Hannon

Boehringer Ingelheim Fonds (PhD Fellowship)

  • M Joaquina Delás

Fundación Bancaria Caixa d'Estalvis i Pensions de Barcelona " (Graduate Studies Fellowship)

  • M Joaquina Delás

National Institutes of Health (R01 HG007650)

  • Andrew D Smith

Damon Runyon Cancer Research Foundation (DRG-2016-12)

  • Leah R Sabin

Howard Hughes Medical Institute (Investigator)

  • Gregory J Hannon

Wellcome Trust (Investigator)

  • Gregory J Hannon

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: For animal experiments conducted at Cold Spring Harbor Laboratory, all the animals were handled according to the approved institutional animal care and use committee (IACUC) protocol (#14-11-18). For animal experiments conducted at CRUK Cambridge Institute, all the animals were handled according to project and personal licenses issued under the United Kingdom Animals (Scientific Procedures) Act, 1986 (PPL 70/8391).

Reviewing Editor

  1. Juan Valcárcel, Centre de Regulació Genòmica (CRG), Barcelona, Spain

Publication history

  1. Received: January 30, 2017
  2. Accepted: September 5, 2017
  3. Accepted Manuscript published: September 6, 2017 (version 1)
  4. Version of Record published: September 28, 2017 (version 2)

Copyright

© 2017, Delás et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. M Joaquina Delás
  2. Leah R Sabin
  3. Egor Dolzhenko
  4. Simon RV Knott
  5. Ester Munera Maravilla
  6. Benjamin T Jackson
  7. Sophia A Wild
  8. Tatjana Kovacevic
  9. Eva Maria Stork
  10. Meng Zhou
  11. Nicolas Erard
  12. Emily Lee
  13. David R Kelley
  14. Mareike Roth
  15. Inês AM Barbosa
  16. Johannes Zuber
  17. John L Rinn
  18. Andrew D Smith
  19. Gregory J Hannon
(2017)
lncRNA requirements for mouse acute myeloid leukemia and normal differentiation
eLife 6:e25607.
https://doi.org/10.7554/eLife.25607

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