IL-1β promotes MPN disease initiation by favoring early clonal expansion ofJAK2-mutant hematopoietic stem cells

Abstract

AbstractJAK2-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 ofJAK2-V617F CHIP to MPN are largely unknown. We hypothesized that IL-1β 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 1-3JAK2-mutant HSCs per recipient. Genetic loss ofIL-1βinJAK2-mutant hematopoietic cells or inhibition by a neutralizing anti-IL-1β antibody restricted the early clonal expansion of theseJAK2-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-1β were associated with damage to sympathetic innervation leading to loss of nestin-positive mesenchymal stromal cells and required the presence ofIL-1R1on bone marrow stromal cells. The anti-IL-1β antibody protected these mesenchymal stromal cells from IL-1β mediated damage and limited the expansion of theJAK2-mutant clone. Our results identify IL-1β as a potential therapeutic target for preventing the transition fromJAK2-V617F CHIP to MPN.Brief summaryIn a mouse model of oligo-clonal myeloproliferative neoplasm (MPN), IL-1β produced byJAK2-mutant cells favored expansion of sub-clinicalJAK2-V617F clones and initiation of MPN disease.