Format

Send to

Choose Destination
Elife. 2018 Nov 9;7. pii: e38314. doi: 10.7554/eLife.38314.

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

Zhu H1,2,3, Zhang L1,2,3, Wu Y1,2,3, Dong B1,2,3, Guo W1,2,3, Wang M1,2,3, Yang L1,2,3, Fan X1,2,3, Tang Y2,4, Liu N5, Lei X2,4, Wu H1,2,3.

Author information

1
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China.
2
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China.
3
Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China.
4
Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China.
5
Drug Discovery Oncology, Bayer Pharmaceuticals, Berlin, 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 β-catenin activation, Spi1 expression and LSC 'stemness' are maintained by a β-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-ALL.

KEYWORDS:

bone marrow; cancer biology; human T-ALL cell line; mouse; regenerative medicine; stem cells; thymus

PMID:
30412053
PMCID:
PMC6251627
DOI:
10.7554/eLife.38314
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for eLife Sciences Publications, Ltd Icon for PubMed Central
Loading ...
Support Center