Shivam Rai, Yang Zhang, Elodie Grockowiak, Quentin Kimmerlin, Nils Hansen, Cedric B. Stoll, Marc Usart, Damien Luque Paz, Hui Hao-Shen, Yexuan Zhu, Julien Roux, Michael S. Bader, Stefan Dirnhofer, Christopher J. Farady, Timm Schroeder, Simón Méndez-Ferrer, Radek C. Skoda

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

  • Hematology
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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 MPN. The factors controlling the conversion of JAK2-V617F CHIP to MPN are largely unknown. We hypothesized that 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 1-3 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. WT recipients transplanted with VF;GFP BM that developed MPN 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 MPN, 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 MPN.

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