IL-10R Inhibition Selects for Jak2V617F Hematopoiesis By Augmenting Inflammation Induced Exhaustion of Wild-Type but Not Jak2V617F Hematopoietic Stem Cells

An emerging theme among clonal hematopoiesis (CH) associated mutations is that these mutations endow hematopoietic stem cells (HSC) protection from chronic inflammatory stress. Specific inflammatory stressors may select for specific mutants, such that presence of particular mutant clones could be leveraged as a biomarker to herald the presence of a specific stressor. JAK2 V617F clonal hematopoiesis is less common among the general aging population but clusters within families suggesting that a specific stressor present among members of myeloproliferative neoplasm (MPN) families selects for JAK2 V617F mutant cells. We have recently found that monocytes from MPN patients and their unaffected family members have defective negative regulation of Toll Like Receptor Ligand (TLR) signaling due to a dampened response to the anti-inflammatory cytokine Interleukin-10 (IL-10) which leads to persistent TLR signaling and increased TNF production.