STING loss attenuates ISG expression without affecting PARP inhibitor sensitivity in Brca1+/− Jak2V617F MPN

Scientific Reports, vol. 16

Abstract

Abstract Myeloproliferative neoplasms (MPN) are characterized by constitutive activation of JAK-STAT signaling, commonly driven by the JAK2 V617F mutation. Previous studies have shown that germline mutations in homologous recombination (HR) repair genes such as BRCA1 may contribute to MPN pathogenesis. We previously demonstrated that Brca1 -haploinsufficiency in Jak2 V617F cells induces replication stress and hypersensitivity to poly (ADP-ribose) polymerase (PARP) inhibition. Here, we directly interrogated the contribution of cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) signaling to replication stress-associated inflammatory responses using genetic ablation of Sting1 , enabling a direct assessment of STING dependency. Using Jak2 V617F -positive 32D cells with Brca1 -haploinsufficiency and Sting1 knockout, we assessed interferon-stimulated gene (ISG) expression and sensitivity to the PARP inhibitor olaparib. Sting1 deletion reduced ISG expression, particularly following olaparib treatment, demonstrating a STING-dependent component of inflammatory signaling in HR-impaired Jak2 V617F cells. However, olaparib-induced ISG expression was not completely abolished by Sting1 loss, indicating the involvement of additional nucleic acid-sensing pathways. Sting1 deficiency also did not alter olaparib-induced effects on proliferation, viability, or apoptosis. These findings refine the role of cGAS-STING signaling in MPN by revealing partial dependence of inflammatory gene expression on STING and suggesting functional redundancy within innate immune signaling networks activated by genomic instability.==

Authors 5

1. Mirjam Hanako Sarholz Aachen Department of Hematology, Oncology Faculty of Medicine

   RWTH Aachen University

   Affiliation as printed

   Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany

   Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany

2. María Jimena Rodriguez Aachen Department of Hematology, Oncology Faculty of Medicine

   RWTH Aachen University

   Affiliation as printed

   Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany

   Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany

3. Tomasz Skórski

   Temple University · Fox Chase Cancer Center

   Affiliation as printed

   Department of Cancer and Cellular Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA

   Fels Cancer Institute for Personalized Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA

   Nuclear Dynamics and Cancer Program, Fox Chase Cancer Center, Philadelphia, PA, USA

4. Steffen Koschmieder corresponding Aachen Department of Hematology, Oncology Faculty of Medicine

   RWTH Aachen University

   Affiliation as printed

   Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany

   Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany

5. Julian Baumeister Aachen Department of Hematology, Oncology Faculty of Medicine

   RWTH Aachen University

   Affiliation as printed

   Center for Integrated Oncology, Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany

   Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany