IL-1β promotes MPN disease initiation by favoring early clonal expansion of JAK2-mutant hematopoietic stem cells

• Published in: Blood advances 2024-03, Vol.8 (5), p.1234-1249
• Main Authors: Rai, Shivam, Zhang, Yang, Grockowiak, Elodie, Kimmerlin, Quentin, Hansen, Nils, Stoll, Cedric B., Usart, Marc, Luque Paz, Damien, Hao-Shen, Hui, Zhu, Yexuan, Roux, Julien, Bader, Michael S., Dirnhofer, Stefan, Farady, Christopher J., Schroeder, Timm, Méndez-Ferrer, Simón, Skoda, Radek C.
• Format: Article
• Language: English
• Subjects: Animals; Animals, Genetically Modified; Bone Marrow Transplantation; Hematopoietic Stem Cells; Interleukin-1beta; Mice; Myeloid Neoplasia; Myeloproliferative Disorders - genetics
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2023011338

•In a mouse model of oligoclonal MPN, IL-1β favors disease initiation by promoting early expansion of a subclinical JAK2-V617F clone.•Anti–IL-1β antibody treatment during the early expansion phase of the JAK2-mutant clone reduced the frequency of MPN disease initiation. [Display omitted] JAK2-V617F is the most frequent somatic mutation causing myeloproliferative neoplasm (MPN). JAK2-V617F can be found in healthy individuals with clonal hematopoiesis of indeterminate potential (CHIP) with a frequency much higher than the prevalence of MPNs. The factors controlling the conversion of JAK2-V617F CHIP to MPN are largely unknown. We hypothesized that interleukin-1β (IL-1β)–mediated inflammation can favor this progression. We established an experimental system using bone marrow (BM) transplantations from JAK2-V617F and GFP transgenic (VF;GFP) mice that were further crossed with IL-1β−/− or IL-1R1−/− mice. To study the role of IL-1β and its receptor on monoclonal evolution of MPN, we performed competitive BM transplantations at high dilutions with only 1 to 3 hematopoietic stem cells (HSCs) per recipient. Loss of IL-1β in JAK2-mutant HSCs reduced engraftment, restricted clonal expansion, lowered the total numbers of functional HSCs, and decreased the rate of conversion to MPN. Loss of IL-1R1 in the recipients also lowered the conversion to MPN but did not reduce the frequency of engraftment of JAK2-mutant HSCs. Wild-type (WT) recipients transplanted with VF;GFP BM that developed MPNs had elevated IL-1β levels and reduced frequencies of mesenchymal stromal cells (MSCs). Interestingly, frequencies of MSCs were also reduced in recipients that did not develop MPNs, had only marginally elevated IL-1β levels, and displayed low GFP-chimerism resembling CHIP. Anti–IL-1β antibody preserved high frequencies of MSCs in VF;GFP recipients and reduced the rate of engraftment and the conversion to MPN. Our results identify IL-1β as a potential therapeutic target for preventing the transition from JAK2-V617F CHIP to MPNs.