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bioRxiv · 10.1101/2023.05.21.541610

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

Rai, S.·Zhang, Y.·Grockowiak, E.·Kimmerlin, Q.·Hansen, N.·Stoll, C. B.·Usart, M.·Hao-Shen, H.·Bader, M. S.·Passweg, J.·Dirnhofer, S.·Farady, C. J.·Schroeder, T.·Mendez-Ferrer, S.·Skoda, R. C.
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Abstract

JAK2-V617F is the most frequent somatic mutation causing myeloproliferative neoplasm (MPN). However, JAK2-V617F can also 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-1{beta} mediated inflammation is one of the factors that favors this progression. We examined mono- or oligoclonal evolution of MPN by performing bone marrow transplantations at limiting dilutions with only 1-3 JAK2-mutant HSCs per recipient. Genetic loss of IL-1{beta} in JAK2-mutant hematopoietic cells or inhibition by a neutralizing anti-IL-1{beta} antibody restricted the early clonal expansion of these JAK2-mutant HSCs resulting in a reduced frequency of a CHIP-like state and a lower rate of conversion to MPN. The MPN disease-promoting effects of IL-1{beta} were associated with damage to sympathetic innervation leading to loss of nestin-positive mesenchymal stromal cells and required the presence of IL-1R1 on bone marrow stromal cells. The anti-IL-1{beta} antibody protected these mesenchymal stromal cells from IL-1{beta} mediated damage and limited the expansion of the JAK2-mutant clone. Our results identify IL-1{beta} as a potential therapeutic target for preventing the transition from JAK2-V617F CHIP to MPN. Brief summaryIn a mouse model of oligo-clonal myeloproliferative neoplasm (MPN), IL-1{beta} produced by JAK2-mutant cells favored expansion of sub-clinical JAK2-V617F clones and initiation of MPN disease.

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Rai, S., Zhang, Y., Grockowiak, E., Kimmerlin, Q., Hansen, N., Stoll, C. B., Usart, M., Hao-Shen, H., Bader, M. S., Passweg, J., Dirnhofer, S., Farady, C. J., Schroeder, T., Mendez-Ferrer, S., Skoda, R. C.. 2023-05-22. IL-1β promotes MPN disease initiation by favoring early clonal expansion of JAK2-mutant hematopoietic stem cells. https://doi.org/10.1101/2023.05.21.541610

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