T-ALL leukemia stem cell 'stemness' is epigenetically controlled by the master regulator SPI1

Abstract
Data availability
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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.

The following data sets were generated

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https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE115356

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Article and author information

Author details

Haichuan Zhu

School of Life Sciences, Peking University, Beijing, China

Competing interests
No competing interests declared.
Liuzhen Zhang

School of Life Sciences, Peking University, Beijing, China

Competing interests
No competing interests declared.
Yilin Wu

School of Life Sciences, Peking University, Beijing, China

Competing interests
No competing interests declared.
Bingjie Dong

School of Life Sciences, Peking University, Beijing, China

Competing interests
No competing interests declared.
Weilong Guo

School of Life Sciences, Peking University, Beijing, China

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-5199-1359
Mei Wang

School of Life Sciences, Peking University, Beijing, China

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0003-3292-1413
Lu Yang

School of Life Sciences, Peking University, Beijing, China

Competing interests
No competing interests declared.
Xiaoying Fan

School of Life Sciences, Peking University, Beijing, China

Competing interests
No competing interests declared.
Yuliang Tang

Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China

Competing interests
No competing interests declared.
Ningshu Liu

Drug Discovery Oncology, Bayer Pharmaceuticals, Berlin, Germany

Competing interests
Ningshu Liu, is an employee of Bayer AG.
Xiaoguang Lei

Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China

Competing interests
No competing interests declared.
Hong Wu

School of Life Sciences, Peking University, Beijing, China

For correspondence
Hongwu@pku.edu.cn

Competing interests
No competing interests declared.

"This ORCID iD identifies the author of this article:" 0000-0001-7545-7919

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.

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).

Copyright

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.