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ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming

Acta Pharmacologica Sinica volume 44, pages 2282–2295 (2023)Cite this article

Abstract

Abnormalities of FGFR1 have been reported in multiple malignancies, suggesting FGFR1 as a potential target for precision treatment, but drug resistance remains a formidable obstacle. In this study, we explored whether FGFR1 acted a therapeutic target in human T-cell acute lymphoblastic leukemia (T-ALL) and the molecular mechanisms underlying T-ALL cell resistance to FGFR1 inhibitors. We showed that FGFR1 was significantly upregulated in human T-ALL and inversely correlated with the prognosis of patients. Knockdown of FGFR1 suppressed T-ALL growth and progression both in vitro and in vivo. However, the T-ALL cells were resistant to FGFR1 inhibitors AZD4547 and PD-166866 even though FGFR1 signaling was specifically inhibited in the early stage. Mechanistically, we found that FGFR1 inhibitors markedly increased the expression of ATF4, which was a major initiator for T-ALL resistance to FGFR1 inhibitors. We further revealed that FGFR1 inhibitors induced expression of ATF4 through enhancing chromatin accessibility combined with translational activation via the GCN2-eIF2α pathway. Subsequently, ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes ASNS, ASS1, PHGDH and SLC1A5, maintaining the activation of mTORC1, which contributed to the drug resistance in T-ALL cells. Targeting FGFR1 and mTOR exhibited synergistically anti-leukemic efficacy. These results reveal that FGFR1 is a potential therapeutic target in human T-ALL, and ATF4-mediated amino acid metabolic reprogramming contributes to the FGFR1 inhibitor resistance. Synergistically inhibiting FGFR1 and mTOR can overcome this obstacle in T-ALL therapy.

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Fig. 1: FGFR1 is upregulated in T-ALL and negatively correlated with the prognosis of patients.
Fig. 2: FGFR1 is a potential therapeutic target in T-ALL but leukemia cells are resistant to FGFR1 inhibitors.
Fig. 3: ATF4 is essential for the resistance of T-ALL against FGFR1 inhibitors.
Fig. 4: Expression of ATF4 is stimulated by increased chromatin accessibility combined with GCN2-mediated translational activation.
Fig. 5: ATF4 is a crucial initiator to upregulate the metabolic genes and remodel the amino acid metabolism.
Fig. 6: Targeting mTOR could overcome the resistance against FGFR1 inhibitors.
Fig. 7: The enhanced amino acid metabolism induced the activation of mTORC1.
Fig. 8: Schematic diagram of the resistance against FGFR1 inhibitors.

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Data availability

The sequence data of RNA-seq and ATAC-seq reported in this study have been deposited in the Genome Sequence Archive (GSA) for human under accession number HRA003406 and HRA003410 respectively. Other published data used in this paper were listed as follows: RNA-seq data of T-ALL cohorts were from Genome Sequence Archive (GSA) for human (HRA000122), Gene Expression Omnibus (GEO) (GSE26713), and database of genotypes and phenotypes (TARGET, phs000464). RNA-seq data about a primary and relapse T-ALL cohort were from NCBI BioProject (PRJNA534488). Survival data of T-ALL were from TARGET, phs000464, and of B-ALL were from TARGET, phs000463. H3K27ac ChIP-seq of Jurkat cells was from Gene Expression Omnibus (GEO), GSE68978. H3K4me3 ChIP-seq of Jurkat cells was from Gene Expression Omnibus (GEO), GSE151297. Data related to this paper could be requested from the corresponding author.

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Acknowledgements

We are obliged to Jian Lin, Long Chen, Nuo Xu (College of Chemistry and Molecular Engineering, Peking University), Hu-dan Liu (Medical Research Institute, Wuhan University), and Yuan Cao, Piao Zou (Analytical & Testing Center, Wuhan University of Science and Technology) for their assistance in the experiments. This work was funded by the grants from the Wuhan Science and Technology Plan Project (2019030703011533) to TCZ, China Postdoctoral Science Foundation (2021M702538), Department of Education of Hubei Province (B2021023), and National Natural Science Foundation of China (82203497) to JPL, and also supported by Natural Science Foundation of Hubei Province (2022CFB029) and National Natural Science Foundation of China (82100193) to HCZ.

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Authors and Affiliations

  1. Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan, 430065, China

    Zi-jian Zhang, Qi-fang Wu, An-qi Ren, Qian Chen, Jiang-zhou Shi, Jia-peng Li, Xi-yu Liu, Zhi-jie Zhang, Yu-zhe Tang, Yuan Zhao, Xiao-yu Zhang, Ge Dong, Mei-jun Xu, Yun-qiang Yue, Jia Hu, Fan Sun, Yu Liu, Tong-cun Zhang & Hai-chuan Zhu

  2. School of Science, Wuhan University of Science and Technology, Wuhan, 430065, China

    Jia-peng Li

  3. Peking-Tsinghua Center for Life Sciences, and Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China

    Ning-ning Yao & Hong Wu

  4. The MOE Key Laboratory of Cell Proliferation and Differentiation, School of Life Sciences, Peking University, Beijing, 100871, China

    Ning-ning Yao & Hong Wu

  5. Department of Medical Records, Office for DRGs (Diagnosis Related Groups), Henan Cancer Hospital, Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, 450003, China

    Chang-peng Liu

  6. Key Lab of Industrial Fermentation Microbiology of the Ministry of Education & Tianjin Key Lab of Industrial Microbiology, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, China

    Jia-xuan Zhao & Tong-cun Zhang

  7. Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Qi-lin Ao

  8. Department of Pathology, School of Basic Medical Science, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Qi-lin Ao

  9. Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, China

    Fu-ling Zhou

  10. College of Life Science, Wuchang University of Technology, Wuhan, 430223, China

    Hai-chuan Zhu

  11. Synergy Innovation Center of Biological Peptide Antidiabetics of Hubei Province, College of Life Science, Wuchang University of Technology, Wuhan, 430223, China

    Hai-chuan Zhu

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  1. Zi-jian Zhang
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Contributions

HCZ, ZJZ, and TCZ designed the experimental plans; ZJZ, AQR, JZS, JPL, XYL, Zhi-jie Zhang, YZT, YZ, NNY, XYZ, CPL, GD, JXZ, MJX, and YY performed the experiments. QFW and QC performed the bioinformatic analysis. ZJZ and HCZ analyzed the data and drafted the manuscript. FS, YL, JH, QLA, FLZ, and HW were involved in the revision of the manuscript.

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Correspondence to Tong-cun Zhang or Hai-chuan Zhu.

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Zhang, Zj., Wu, Qf., Ren, Aq. et al. ATF4 renders human T-cell acute lymphoblastic leukemia cell resistance to FGFR1 inhibitors through amino acid metabolic reprogramming. Acta Pharmacol Sin 44, 2282–2295 (2023). https://doi.org/10.1038/s41401-023-01108-4

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