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Elife. 2017 Sep 6;6. pii: e25607. doi: 10.7554/eLife.25607.

lncRNA requirements for mouse acute myeloid leukemia and normal differentiation.

Author information

1
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom.
2
Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York, United States.
3
Molecular and Computational Biology, University of Southern California, Los Angeles, United States.
4
German Cancer Research Center, Heidelberg, Germany.
5
Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, United States.
6
Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
7
New York Genome Center, New York, United States.
#
Contributed equally

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 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.

KEYWORDS:

c-Myc; chromosomes; developmental biology; genes; hematopoiesis; leukemia; lncRNA; mouse; stem cells

PMID:
28875933
PMCID:
PMC5619947
DOI:
10.7554/eLife.25607
[Indexed for MEDLINE]
Free PMC Article

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