lncRNA requirements for mouse acute myeloid leukemia and normal differentiation
- Cold Spring Harbor Laboratory, United States
- University of Southern California, United States
- University of Cambridge, United Kingdom
- Watson School of Biological Sciences, United States
- Harvard University, United States
- Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Austria
- 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.
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Author details
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
- Juan Valcárcel, Centre de Regulació Genòmica (CRG), Barcelona, Spain
Publication history
- Received: January 30, 2017
- Accepted: September 5, 2017
- Accepted Manuscript published: September 6, 2017 (version 1)
- 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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lncRNA requirements for mouse acute myeloid leukemia and normal differentiation
eLife 6:e25607.
https://doi.org/10.7554/eLife.25607
Further reading
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- Developmental Biology
- Evolutionary Biology
Development of tooth shape is regulated by the enamel knot signalling centre, at least in mammals. Fgf signalling regulates differential proliferation between the enamel knot and adjacent dental epithelia during tooth development, leading to formation of the dental cusp. The presence of an enamel knot in non-mammalian vertebrates is debated given differences in signalling. Here, we show the conservation and restriction of fgf3, fgf10, and shh to the sites of future dental cusps in the shark (Scyliorhinus canicula), whilst also highlighting striking differences between the shark and mouse. We reveal shifts in tooth size, shape, and cusp number following small molecule perturbations of canonical Wnt signalling. Resulting tooth phenotypes mirror observed effects in mammals, where canonical Wnt has been implicated as an upstream regulator of enamel knot signalling. In silico modelling of shark dental morphogenesis demonstrates how subtle changes in activatory and inhibitory signals can alter tooth shape, resembling developmental phenotypes and cusp shapes observed following experimental Wnt perturbation. Our results support the functional conservation of an enamel knot-like signalling centre throughout vertebrates and suggest that varied tooth types from sharks to mammals follow a similar developmental bauplan. Lineage-specific differences in signalling are not sufficient in refuting homology of this signalling centre, which is likely older than teeth themselves.
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- Developmental Biology
- Evolutionary Biology
The tooth shape of sharks and mice are regulated by a similar signaling center despite their teeth having very different geometries.
