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Fabp4 is essential for the maintenance of leukemia stem cells while sparing hematopoietic stem cells

Leukemia volume 39, pages 1512–1515 (2025)Cite this article

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Fatty Acid Binding Protein 4 (FABP4) is a key player among the fatty acid-binding protein family. It exhibits a high level of expression specifically in adipocytes, immune cells, and endothelial cells. Serving as a lipid chaperone, FABP4 is essential for the metabolic processing of fatty acids, including their breakdown, transport, and storage [1, 2]. Additionally, it significantly contributes to the development of various metabolic disorders [3]. Extensive research has shown that FABP4 is instrumental in the pathogenesis of conditions such as diabetes, non-alcoholic fatty liver disease, and atherosclerosis [4,5,6]. In the realm of oncology, recent findings have revealed that FABP4 is frequently upregulated in numerous malignant tumors. It exerts a substantial influence on tumorigenesis, metastasis, and the acquisition of drug resistance [7]. Despite advancements, the role of FABP4 in hematopoietic and leukemia stem cells remains unexplored, highlighting a significant gap in current scientific literature.

Single-cell RNA sequencing (scRNA-seq) was conducted on BM cells harvested from primary recipient mice of MA9-WT, MA9-HET, and MA9-KO to investigate Fabp4’s role in LSCs. The gene set machine annotation, complemented by manual curation, pinpointed cluster 10 as enriched for LSCs (Fig. S5A-E). Analysis of the sequencing data indicated a significant decrease in the presence of LSCs among MA9-HET and MA9-KO mice when compared with their MA9-WT counterparts, with a concurrent increase in mature cell clusters (Fig. 2F–H). A stark divergence in the transcriptome profile was evident of all BM cells between WT and HET_KO groups, with tumor development-associated genes such as Ikzf2, Igkc, Satb1, Mt1, Pbx3, etc., being significantly downregulated in the HET_KO cohort (Fig. S6A). Notably, pathways essential for hematopoietic cell maturation, including hematopoietic cell lineage, Th1, Th2, and Th17 cell differentiation, were upregulated in HET_KO compared to WT (Fig. S6B). Conversely, the transcriptional misregulation in cancers was notably downregulated (Figure S6C). In our comparative analysis of differentially expressed genes between HET_KO and WT, the heatmap in Fig. S6D depicted a significant downregulation of tumor progression-related genes, including TCF4, Gadd45b, Mt1, Gtf2b, etc., in the LSCs of from HET and KO recipient mice. Gene set enrichment analysis (GSEA) revealed notable downregulation of oxidative phosphorylation (OXPHOS) and arginine biosynthesis in LSCs from HET and KO mice (Fig. S6E-F). Extensive research has implicated OXPHOS upregulation in leukemia, with OXPHOS inhibition shown to selectively target dormant LSCs [11]. Arginine, central to tumor growth, invasion, angiogenesis, and immune modulation, serves as a crucial intermediate in the production of compounds associated with cancer [12]. These findings suggest that Fabp4 deficiency induces LSC dysfunction, thereby impeding the progression of AML.

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Fig. 1: Depletion of Fabp4 does not affect hematopoiesis.
Fig. 2: Fabp4 is vital for the maintenance of LSCs.

Data availability

The scRNA-seq data from this research is publicly available in the GEO database under the accession number GSE278587. The RNA-seq data from LSCs is publicly available in the GEO database under the accession number GSE289635. The LC-MS metabolomics data from LSCs is publicly available in the GSA database under the accession number OMIX009027.

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Funding

This research was funded in part by the National Key R&D Program of China (2024YFC2510500), National Natural Science Foundation of China (32270791, 82070175, 82370128), the Scientific Research Project of Hunan Provincial Health Commission (C202303046332), the Scientific Research Project of Hunan Provincial Department of Education (23A0018), Huxiang Youth Talent Support Program (2022RC1205), International Centre for Genetic Engineering and Biotechnology-ICGEB (CRP/CHN22-03_EC) and the American Society of Hematology.

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Author notes

  1. These authors contributed equally: Cheng Xing, Huifang Zhang.

Authors and Affiliations

  1. Department of Hematology, The Second Xiangya Hospital, Molecular Biology Research Center, School of Life Sciences, Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, China

    Cheng Xing, Huifang Zhang, Mengqiu Zheng, Qian Lu, Yujia Tao, Shina Xu, Long Liang, Hongling Peng & Yue Sheng

  2. Hunan Engineering Research Center of Targeted therapy for Hematopoietic Malignancies, Changsha, Hunan, China

    Cheng Xing, Huifang Zhang, Mengqiu Zheng, Qian Lu, Yujia Tao, Shina Xu, Long Liang, Hongling Peng & Yue Sheng

  3. National Clinical Research Center for Metabolic Diseases, Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Yang Xiao

  4. Department of Orthopaedics, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China

    Haodong Xu

  5. Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Shuqian Xu

  6. Furong Laboratory, Changsha, Hunan, China

    Yue Sheng

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  1. Cheng Xing
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Contributions

YS, HP, and YX designed the study. CX, HZ, MZ, YT and QL conducted the experiments. CX, HZ, SX, HX, LL and SX analyzed the data. CX and YS drafted the manuscript, with all authors contributing to its critical review.

Corresponding authors

Correspondence to Shuqian Xu, Hongling Peng or Yue Sheng.

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The authors declare that they have no competing interests.

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All methods were performed in accordance with the relevant guidelines and regulations. The Animal Care and Use Committee of the Second Xiangya Hospital granted approval for all animal experiments (Approve number: 2021679).

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Xing, C., Zhang, H., Zheng, M. et al. Fabp4 is essential for the maintenance of leukemia stem cells while sparing hematopoietic stem cells. Leukemia 39, 1512–1515 (2025). https://doi.org/10.1038/s41375-025-02568-9

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