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NORMAL HEMATOPOIESIS

STAT3 protects hematopoietic stem cells by preventing activation of a deleterious autocrine type-I interferon response

Leukemia (2024)Cite this article

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Abstract

Hematopoietic stem and progenitor cells (HSPCs) maintain blood-forming and immune activity, yet intrinsic regulators of HSPCs remain elusive. STAT3 function in HSPCs has been difficult to dissect as Stat3-deficiency in the hematopoietic compartment induces systemic inflammation, which can impact HSPC activity. Here, we developed mixed bone marrow (BM) chimeric mice with inducible Stat3 deletion in 20% of the hematopoietic compartment to avoid systemic inflammation. Stat3-deficient HSPCs were significantly impaired in reconstitution ability following primary or secondary bone marrow transplantation, indicating hematopoietic stem cell (HSC) defects. Single-cell RNA sequencing of Lin−ckit+Sca1+ BM cells (LSKs) revealed aberrant activation of cell cycle, p53, and interferon (IFN) pathways in Stat3-deficient HSPCs. Stat3-deficient LSKs accumulated γH2AX and showed increased expression of DNA sensors and type-I IFN (IFN-I), while treatment with A151-ODN inhibited expression of IFN-I and IFN-responsive genes. Further, the blockade of IFN-I receptor signaling suppressed aberrant cell cycling, STAT1 activation, and nuclear p53 accumulation. Collectively, our results show that STAT3 inhibits a deleterious autocrine IFN response in HSCs to maintain long-term HSC function. These data signify the importance of ensuring therapeutic STAT3 inhibitors are targeted specifically to diseased cells to avoid off-target loss of healthy HSPCs.

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Fig. 1: Stat3-deficient HSPCs show ineffective hematopoietic activity in the absence of systemic inflammation.
Fig. 2: Stat3-deficient HSPCs show reduced competitive advantage.
Fig. 3: STAT3 is required to maintain HSC function.
Fig. 4: Stat3-deficient LSKs have a unique transcriptional profile and myeloid-biased gene expression.
Fig. 5: Cell cycle deregulation, p53 activation, and DNA damage in Stat3-deficient LSKs.
Fig. 6: STAT3 prevents p53 activation in LSKs by inhibiting autocrine IFN signaling.

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Data availability

All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. The scRNA-seq data have been submitted to the NCBI GEO repository and are accessible through accession number (GSE220466).

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Acknowledgements

We thank Joseph Munch for his review and edits to this manuscript. This work was supported by grants from the Cancer Prevention and Research Institute of Texas (CPRIT) (Research Training award RP170067, RLB) (Research Training awards RP170067 and RP210028, LMK and EMP), the National Institutes of Health (NIH) (F32 CA271513, EMP; R35 CA197566, FGG and DK; R01AI133822 and R56AI109294-06, SSW). SC is a Scholar of the Leukemia and Lymphoma Society. This work used MD Anderson’s Advanced Technology Genomics Core (supported by NIH 1S10OD024977-01 and NCI P30CA0166722), Research Histology Core Laboratory (supported by NCI P30CA0166722), Advanced Microscopy Core (supported by NIH S10RR029552), and Advanced Cytometry & Sorting Facility (supported by NCI P30CA0166722).

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Authors and Affiliations

  1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Bhakti Patel, Yifan Zhou, Rachel L. Babcock, Yusra B. Medik, Laura M. Kahn, Josué E. Pineda, Elizabeth M. Park, Sarah M. Schneider & Stephanie S. Watowich

  2. MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    Rachel L. Babcock, Laura M. Kahn, Josué E. Pineda, Sarah M. Schneider & Stephanie S. Watowich

  3. Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA

    Feiyang Ma

  4. Division of Rheumatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA

    Feiyang Ma

  5. Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    M. Anna Zal, Tomasz Zal & Simona Colla

  6. Herbert Irving Cancer Center and Department of Genetics and Development, Columbia University, New York, NY, USA

    Dhiraj Kumar & Filippo G. Giancotti

  7. Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Elizabeth M. Park

  8. Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Ximing Tang & Maria Gabriela Raso

  9. Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Collene R. Jeter

  10. Department of Stem Cell Transplantation and Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Karen Clise-Dwyer

  11. Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Khandan Keyomarsi

  12. Program for Innovative Microbiome and Translational Research (PRIME-TR), The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Stephanie S. Watowich

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  1. Bhakti Patel
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Contributions

BP designed experiments, performed experiments, analyzed data, prepared data for presentation, and wrote the manuscript. YZ, RLB, YBM, LMK, JEP, and EMP assisted with sample collection and data analysis. DK assisted with scRNA-seq studies and analyzed data. FM curated scRNA-seq data, analyzed the results, and prepared data for presentation. MAZ, CRJ, and TZ assisted with confocal microscopy and Imaris analysis. MGR and XT performed pathology assessments. SMS and KC-D assisted with flow cytometry data analysis. KK provided advice and reviewed cell cycle data. FGG provided advice on scRNA-seq data analyses. SC analyzed scRNA-seq data, performed validation, provided advice on data interpretation and presentation. SSW conceptualized the study, designed experiments, procured funding, supervised the study, and wrote the manuscript.

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Correspondence to Stephanie S. Watowich.

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Patel, B., Zhou, Y., Babcock, R.L. et al. STAT3 protects hematopoietic stem cells by preventing activation of a deleterious autocrine type-I interferon response. Leukemia (2024). https://doi.org/10.1038/s41375-024-02218-6

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