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-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 1-3 JAK2-mutant HSCs per recipient. Genetic loss of IL-1β in JAK2-mutant hematopoietic cells or inhibition by a neutralizing anti-IL-1β 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-1β 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-1β antibody protected these mesenchymal stromal cells from IL-1β mediated damage and limited the expansion of the JAK2-mutant clone. Our results identify IL-1β as a potential therapeutic target for preventing the transition from JAK2-V617F CHIP to MPN.
Brief summary In a mouse model of oligo-clonal myeloproliferative neoplasm (MPN), IL-1β produced by JAK2-mutant cells favored expansion of sub-clinical JAK2-V617F clones and initiation of MPN disease.
Competing Interest Statement
R.C.S. is a scientific advisor/SAB member and has equity in Ajax Therapeutics, he consulted for and/or received honoraria from Novartis, BMS/Celgene, AOP, GSK, Baxalta and Pfizer. N.H. owns stocks in the company Cantargia. C.J.F. is a full-time employee of Novartis Pharma AG. The anti-IL-1β antibody studies were carried out in the laboratory of R.C.S. with the antibody provided by Novartis. The remaining authors declare no competing financial interests