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

  1. Haichuan Zhu
  2. Liuzhen Zhang
  3. Yilin Wu
  4. Bingjie Dong
  5. Weilong Guo
  6. Mei Wang
  7. Lu Yang
  8. Xiaoying Fan
  9. Yuliang Tang
  10. Ningshu Liu
  11. Xiaoguang Lei
  12. Hong Wu  Is a corresponding author
  1. Peking University, China
  2. 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.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Haichuan Zhu

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
  2. Liuzhen Zhang

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
  3. Yilin Wu

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
  4. Bingjie Dong

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
  5. Weilong Guo

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5199-1359
  6. Mei Wang

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3292-1413
  7. Lu Yang

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
  8. Xiaoying Fan

    School of Life Sciences, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
  9. Yuliang Tang

    Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
  10. Ningshu Liu

    Drug Discovery Oncology, Bayer Pharmaceuticals, Berlin, Germany
    Competing interests
    Ningshu Liu, is an employee of Bayer AG.
  11. Xiaoguang Lei

    Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
    Competing interests
    No competing interests declared.
  12. Hong Wu

    School of Life Sciences, Peking University, Beijing, China
    For correspondence
    Hongwu@pku.edu.cn
    Competing interests
    No competing interests declared.
    ORCID icon "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).

Reviewing Editor

  1. A Thomas Look, Harvard Medical School, United States

Publication history

  1. Received: May 13, 2018
  2. Accepted: November 9, 2018
  3. Accepted Manuscript published: November 9, 2018 (version 1)
  4. 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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  1. Haichuan Zhu
  2. Liuzhen Zhang
  3. Yilin Wu
  4. Bingjie Dong
  5. Weilong Guo
  6. Mei Wang
  7. Lu Yang
  8. Xiaoying Fan
  9. Yuliang Tang
  10. Ningshu Liu
  11. Xiaoguang Lei
  12. Hong Wu
(2018)
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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