Publications
SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming
Xi Xu, Yanhui Yu, Wenwen Zhang, Weiwei Ma, Chong He, Guo Qiu, Xinyi Wang, Qiong Liu, Minyi Zhao, Jiayi Xie, Fang Tao, John M. Perry, Qifa Liu, Shuan Rao, Xunlei Kang, Meng Zhao, Linjia Jiang
Leukaemia stem cells (LSCs) in acute myeloid leukaemia present a considerable treatment challenge due to their resistance to chemotherapy and immunosurveillance. The connection between these properties in LSCs remains poorly understood. Here we demonstrate that inhibition of tyrosine phosphatase SHP-1 in LSCs increases their glycolysis and oxidative phosphorylation, enhancing their sensitivity to chemotherapy and vulnerability to immunosurveillance. Mechanistically, SHP-1 inhibition leads to the upregulation of phosphofructokinase platelet (PFKP) through the AKT–β-catenin pathway. The incre...
A Ferroptosis-Inducing and Leukemic Cell-Targeting Drug Nanocarrier Formed by Redox-Responsive Cysteine Polymer for Acute Myeloid Leukemia Therapy
Yanhui Yu, Yabin Meng, Xi Xu, Tong Tong, Chong He, Liying Wang, Kaitao Wang, Minyi Zhao, Xinru You, Wenwen Zhang, Linjia Jiang, Jun Wu, and Meng Zhao
Ferroptosis is an alternative strategy to overcome chemoresistance, but effective therapeutic approaches to induce ferroptosis for acute myeloid leukemia (AML) treatment are limited. Here, we developed glutathione (GSH)-responsive cysteine polymer-based ferroptosis-inducing nanomedicine (GCFN) as an efficient ferroptosis inducer and chemotherapeutic drug nanocarrier for AML treatment. GCFN depleted intracellular GSH and inhibited glutathione peroxidase 4, a GSH-dependent hydroperoxidase, to cause lipid peroxidation and ferroptosis in AML cells. Furthermore, GCFN-loaded paclitaxel (PTX@GCFN) ta...
PD-1 signalling defines and protects leukaemic stem cells from T cell receptor-induced cell death in T cell acute lymphoblastic leukaemia
Xi Xu, Wenwen Zhang, Li Xuan, Yanhui Yu, Wen Zheng, Fang Tao, Jacqelyn Nemechek, Chong He, Weiwei Ma, Xue Han, Siyu Xie, Minyi Zhao, Jian Wang, Yuhua Qu, Qifa Liu, John M. Perry, Linjia Jiang, Meng Zhao
T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive malignancy with poor prognosis, but a decisive marker and effective treatment for leukaemia stem cells (LSCs) remain unclear. Here, using lineage tracing, limiting dilution assays and in vivo live imaging approaches, we identify rare inhibitory receptor programmed cell death 1 (PD-1)-expressing cells that reside at the apex of leukaemia hierarchy for initiation and relapse in T-ALL. Ablation of PD-1-expressing cells, deletion of PD-1 in T-ALL cells or blockade of PD-1 or PD-1 ligand 1 significantly eradicated LSCs and suppress...
Loss of sphingosine kinase promotes the expansion of hematopoietic stem cells by improving their metabolic fitness
Changzheng Li, Binghuo Wu, Yishan Li, Yaxi Liu, Jin Wang, Jiayi Xie, Xi Xu, Xiaobin Tian, Zhitao Ye, Jingjing Guan, Jie Chen, Siyu Xie, Baolin Zhang,Boyong Cai, Qianhao Wang, Haopeng Yu, Tian Lan, Cheuk Him Man, Xunlei Kang, Pengxu Qian, John M. Perry, Aibin He, Linjia Jiang, Meng Zhao
Hematopoietic stem cells (HSCs) have reduced capacities to properly maintain and replenish the hematopoietic system during myelosuppressive injury or aging. Expanding and rejuvenating HSCs for therapeutic purposes has been a long-sought goal with limited progress. Here, we show that the enzyme Sphk2 (sphingosine kinase 2), which generates the lipid metabolite sphingosine-1-phosphate, is highly expressed in HSCs. The deletion of Sphk2 markedly promotes self-renewal and increases the regenerative potential of HSCs. More importantly, Sphk2 deletion globally preserves the young HSC gene expression...
Amino acid catabolism regulates hematopoietic stem cell proteostasis via a GCN2-eIF2a axis
Changzheng Li, Binghuo Wu, Yishan Li, Jie Chen, Zhitao Ye, Xiaobin Tian, Jin Wang, Xi Xu, Shuai Pan, Yucan Zheng, Xiongwei Cai, Linjia Jiang, Meng Zhao
Hematopoietic stem cells (HSCs) adapt their metabolism to maintenance and proliferation; however, the mechanism remains incompletely understood. Here, we demonstrated that homeostatic HSCs exhibited high amino acid (AA) catabolism to reduce cellular AA levels, which activated the GCN2-eIF2α axis, a protein synthesis inhibitory checkpoint to restrain protein synthesis for maintenance. Furthermore, upon proliferation conditions, HSCs enhanced mitochondrial oxidative phosphorylation (OXPHOS) for higher energy production but decreased AA catabolism to accumulate cellular AAs, which inactivated th...
The RIG-I-NRF2 axis regulates the mesenchymal stromal niche for bone marrow transplantation
Qi Lou, Kaizheng Jiang, Quanhui Xu, Lisha Yuan, Siyu Xie, Yuan Pan, Jian Chen, Jun Wu, Jiang Zhu, Linjia Jiang, Meng Zhao
Bone marrow–derived mesenchymal stem cells (BMSCs) support bone formation and constitute the stromal niche in regulating hematopoietic stem cells (HSCs). Stromal niche dysfunction affects HSC engraftment during transplantation; however, the underlying mechanisms remain elusive. In the present study, we found that all-trans retinoic acid (ATRA) and inflammation stress upregulated retinoic acid–inducible gene I (RIG-I) in BMSCs. Excess RIG-I expression damaged the clonogenicity, bone-forming ability of BMSCs and particularly their stromal niche function that supports HSC expansion in vitro a...
A self-assembled leucine polymer sensitizes leukemic stem cells to chemotherapy by inhibiting autophagy in acute myeloid leukemia
Xi Xu, Jian Wang, Tong Tong, Wenwen Zhang, Jin Wang, Weiwei Ma, ShunqingWang, Dunhua Zhou, Jun Wu, Linjia Jiang, Meng Zhao
Chemotherapy is the primary treatment option for acute myeloid leukemia (AML), but leukemic stem cells (LSC) can survive chemotherapy for disease recurrence and refractory. Here, we found that AML cells obtained from relapsed patients had increased autophagy levels than de novo AML cells. Furthermore, doxorubicin (DOX) treatment stimulated autophagy in LSC by repressing the mTOR pathway, and pharmaceutical inhibition of autophagy rendered chemoresistant LSC sensitive to DOX treatment in MLL-AF9 induced murine AML. Moreover, we developed a self-assembled leucine polymer, which activated mTOR to...
A metabolic reprogramming amino acid polymer as an immunosurveillance activator and leukemia targeting drug carrier for T-cell acute lymphoblastic leukemia
Changzheng Li, Xinru You, Xi Xu, Binghuo Wu, Yuye Liu, Tong Tong, Jie Chen, Yishan Li, Chunlei Dai, Zhitao Ye, Xiaobin Tian, Yan Wei, Zechen Hao, Linjia Jiang, Jun Wu, Meng Zhao
Compromised immunosurveillance leads to chemotherapy resistance and disease relapse of hematological malignancies. Amino acid metabolism regulates immune responses and cancer; however, a druggable amino acid metabolite to enhance antitumor immunosurveillance and improve leukemia targeting-therapy efficacy remains unexplored. Here, an L-phenylalanine polymer, Metabolic Reprogramming Immunosurveillance Activation Nanomedicine (MRIAN), is invented to effectively target bone marrow (BM) and activate the immune surveillance in T-cell acute lymphoblastic leukemia (T-ALL) by inhibiting myeloid-derive...