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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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).
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
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