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

Bhakti Patel; Yifan Zhou; Rachel L Babcock; Feiyang Ma; M Anna Zal; Dhiraj Kumar; Yusra B Medik; Laura M Kahn; Josué E Pineda; Elizabeth M Park; Sarah M Schneider; Ximing Tang; Maria Gabriela Raso; Collene R Jeter; Tomasz Zal; Karen Clise-Dwyer; Khandan Keyomarsi; Filippo G Giancotti; Simona Colla; Stephanie S Watowich

doi:10.1038/s41375-024-02218-6

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

Leukemia. 2024 Mar 11. doi: 10.1038/s41375-024-02218-6. Online ahead of print.

Authors

Bhakti Patel¹, Yifan Zhou¹, Rachel L Babcock^{1

2}, Feiyang Ma^{3

4}, M Anna Zal⁵, Dhiraj Kumar⁶, Yusra B Medik¹, Laura M Kahn^{1

2}, Josué E Pineda^{1

2}, Elizabeth M Park^{1

7}, Sarah M Schneider^{1

2}, Ximing Tang⁸, Maria Gabriela Raso⁸, Collene R Jeter⁹, Tomasz Zal⁵, Karen Clise-Dwyer¹⁰, Khandan Keyomarsi¹¹, Filippo G Giancotti⁶, Simona Colla⁵, Stephanie S Watowich^{12

13

14}

Affiliations

¹ Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
³ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Division of Rheumatology, Department of Internal Medicine, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.
⁵ Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁶ Herbert Irving Cancer Center and Department of Genetics and Development, Columbia University, New York, NY, USA.
⁷ Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁸ Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
⁹ Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Department of Stem Cell Transplantation and Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹¹ Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹² Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. swatowic@mdanderson.org.
¹³ MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA. swatowic@mdanderson.org.
¹⁴ Program for Innovative Microbiome and Translational Research (PRIME-TR), The University of Texas MD Anderson Cancer Center, Houston, TX, USA. swatowic@mdanderson.org.

PMID: 38467768
DOI: 10.1038/s41375-024-02218-6

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.

Abstract

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