lncRNA requirements for mouse acute myeloid leukemia and normal differentiation.
M Joaquina DelásLeah R SabinEgor DolzhenkoSimon Rv KnottEster Munera MaravillaBenjamin T JacksonSophia A WildTatjana KovacevicEva Maria StorkMeng ZhouNicolas ErardEmily LeeDavid R KelleyMareike RothInês Am BarbosaJohannes ZuberJohn L RinnAndrew D SmithGregory James HannonPublished in: eLife (2017)
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.
Keyphrases
- acute myeloid leukemia
- long non coding rna
- bone marrow
- transcription factor
- network analysis
- allogeneic hematopoietic stem cell transplantation
- genome wide identification
- stem cells
- genome wide analysis
- poor prognosis
- mesenchymal stem cells
- long noncoding rna
- genome wide
- high throughput
- high glucose
- dna methylation
- diabetic rats
- oxidative stress
- drug induced
- big data
- single cell
- endothelial cells
- acute lymphoblastic leukemia
- cell therapy
- heat stress
- binding protein
- heat shock
- hematopoietic stem cell