T-ALL leukemia stem cell 'stemness' is epigenetically controlled by the master regulator SPI1
Haichuan Zhu,
Liuzhen Zhang,
Yilin Wu,
Bingjie Dong,
Weilong Guo,
Mei Wang,
Lu Yang,
Xiaoying Fan,
Yuliang Tang,
Ningshu Liu,
Xiaoguang Lei,
Hong Wu
Affiliations
Haichuan Zhu
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China
Liuzhen Zhang
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China
Yilin Wu
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China
Bingjie Dong
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China
Lu Yang
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China
Xiaoying Fan
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China
Yuliang Tang
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
Ningshu Liu
Drug Discovery Oncology, Bayer Pharmaceuticals, Berlin, Germany
Xiaoguang Lei
Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Department of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing, China
The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China; Beijing Advanced Innovation Center for Genomics, Peking University, Beijing, China
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.
