T-ALL leukemia stem cell 'stemness' is epigenetically controlled by the master regulator SPI1
- Peking University, China
- Bayer Pharmaceuticals, Germany
Abstract
Leukemia stem cells (LSCs) are regarded as the origins and key therapeutic targets of leukemia, but limited knowledge is available on the key determinants of LSC 'stemness'. Using single-cell RNA-seq analysis, we identify a master regulator, SPI1, the LSC-specific expression of which determines the molecular signature and activity of LSCs in the murine Pten-null T-ALL model. Although initiated by PTEN-controlled b-catenin activation, Spi1 expression and LSC 'stemness' are maintained by a b-catenin-SPI1-HAVCR2 regulatory circuit independent of the leukemogenic driver mutation. Perturbing any component of this circuit either genetically or pharmacologically can prevent LSC formation or eliminate existing LSCs. LSCs lose their 'stemness' when Spi1 expression is silenced by DNA methylation, but Spi1 expression can be reactivated by 5-AZ treatment. Importantly, similar regulatory mechanisms may be also present in human T-ALLs.
Data availability
All the Bulk RNA-seq, Single cell RNA-seq and BiSulfite-seq data for this study are deposited in NCBI Gene Expression Omnibus under the accession number GSE115356.
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T-ALL Leukemia Stem CellNCBI Gene Expression Omnibus, GSE115356.
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Therapeutically Applicable Research to Generate Effective TreatmentsNCBI database of Genotypes and Phenotypes (dbGaP), phs000464.
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Gene Expression Profile of 57 human T-ALL samples collected in human clinical trial E2993NCBI Gene Expression Omnibus, GSE33469.
Article and author information
Author details
Funding
Peking-tsinghua Center for Life science
- Hong Wu
Beijing Advanced Innovation Center for Genomics
- Hong Wu
Bayer Pharma
- Hong Wu
National Key Research (Grant No. 2017YFA0505200)
- Xiaoguang Lei
National Science Foundation of China
- Lu Yang
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- A Thomas Look, Harvard Medical School, United States
Ethics
Animal experimentation: All experimental protocols were approved by the Peking University Animal Care and Use Committee (IACUC).This study were approved by the Peking University Animal Care and Use Committee (LSC-WuH-1).
Version history
- Received: May 13, 2018
- Accepted: November 9, 2018
- Accepted Manuscript published: November 9, 2018 (version 1)
- Version of Record published: November 23, 2018 (version 2)
Copyright
© 2018, Zhu 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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T-ALL leukemia stem cell 'stemness' is epigenetically controlled by the master regulator SPI1
eLife 7:e38314.
https://doi.org/10.7554/eLife.38314
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