Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom; Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York, United States
Leah R Sabin
Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York, United States
Egor Dolzhenko
Molecular and Computational Biology, University of Southern California, Los Angeles, United States
Simon RV Knott
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom; Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York, United States
Ester Munera Maravilla
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom
Benjamin T Jackson
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom
Sophia A Wild
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom; German Cancer Research Center, Heidelberg, Germany
Tatjana Kovacevic
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom
Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, United Kingdom; Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, New York, United States; New York Genome Center, New York, United States
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.
