STAT3 protects HSCs from intrinsic interferon signaling and loss of long-term blood-forming activity

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

doi:10.1101/2023.02.10.528069

STAT3 protects HSCs from intrinsic interferon signaling and loss of long-term blood-forming activity

bioRxiv [Preprint]. 2023 Feb 11:2023.02.10.528069. doi: 10.1101/2023.02.10.528069.

Authors

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

2}, Feiyang Ma^{3

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

2}, Josué E Pineda^{1

2}, Elizabeth M Park^{1

7}, Ximing Tang⁸, Maria Gabriela Raso⁸, Tomasz Zal⁵, Karen Clise-Dwyer⁹, Filippo G Giancotti⁶, Simona Colla⁵, Stephanie S Watowich^{1

2

10}

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 Stem Cell Transplantation and Hematopoietic Biology and Malignancy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
¹⁰ Program for Innovative Microbiome and Translational Research (PRIME-TR), The University of Texas MD Anderson Cancer Center, Houston, TX, US.

Abstract

STAT3 function in hematopoietic stem and progenitor cells (HSPCs) has been difficult to discern as Stat3 deficiency in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. To address this, we established mixed bone marrow (BM) chimeric mice with CreER-mediated Stat3 deletion in 20% of the hematopoietic compartment. Stat3-deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM in contrast to Stat3-sufficient (CreER) controls. Single-cell RNA sequencing of Lin^-ckit⁺Sca1⁺ BM cells revealed altered transcriptional responses in Stat3-deficient hematopoietic stem cells (HSCs) and multipotent progenitors, including intrinsic activation of cell cycle, stress response, and interferon signaling pathways. Consistent with their deregulation, Stat3-deficient Lin^-ckit⁺Sca1⁺ cells accumulated γH2AX over time. Following secondary BM transplantation, Stat3-deficient HSPCs failed to reconstitute peripheral blood effectively, indicating a severe functional defect in the HSC compartment. Our results reveal essential roles for STAT3 in HSCs and suggest the potential for using targeted synthetic lethal approaches with STAT3 inhibition to remove defective or diseased HSPCs.

Keywords: DNA damage; IFN signaling; STAT3; cell cycle; hematopoietic stem cell.

Publication types

Preprint

Abstract

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