Myeloproliferative Neoplasm (MPNs) are a group of chronic blood cancers characterized by the expansion of a mutant clone with constitutive activation of JAK/STAT signaling, resulting in an overproduction of myeloid cells. MPN patients have an increased risk of thrombosis and transformation to acute leukemia. There is no cure for MPN besides bone marrow transplantation, and current treatments only alleviate symptom burden and reduce thrombotic risk. Of the stem cell derived mutations identified in MPN, JAK2V617F is the most common acquired driver mutation in hematopoietic stem cell (HSC). Interestingly, several groups including our lab have demonstrated that the Jak2V617F HSCs do not have a selective advantage over wild-type HSC. In order for a JAK2V617F HSC to expand and cause disease, it must have gained a selective advantage to outcompete normal HSC. This suggests that specific environmental pressures must be present for JAK2V617F mutant cells to gain a selective advantage, outcompete their normal counterparts and expand to cause an MPN. Chronic inflammation is a key feature of MPN. Inflammation not only drives many of the debilitating symptoms associated with MPN such as severe itching and fatigue, but also provides an environment that is advantageous to MPN mutant HSC. The mechanism driving chronic inflammation in MPN is currently unknown. Therefore, by understanding the underlying cause of inflammation that drives the pathogenesis of MPN, we could provide better therapeutic targets and prevention for disease development. This work addresses what causes exaggerated inflammatory cytokine productions and its role in clonal expansion of mutant HSC in MPN patients. We have found that monocytes from MPN patients have impaired IL-10R signaling, which normally serves to reduce inflammation. This results in the inability of MPN monocytes to dampen pro-inflammatory cytokine, TNF-α. We have also found that the overproduction of TNF-α and IL-10R signaling defect are independent of the Jak2V617F mutant cells, suggesting that there may be a genetic feature of those predisposed to acquire MPN. Using a Jak2V617F knock-in mouse model, where the Jak2V617F mutant HSCs do not normally have a selective advantage over WT HSCs, we have found that blocking IL-10R provide a selective advantage for clonal expansion. Collectively, these studies suggest that the IL-10R signaling defects in MPN patients plays an important role for clonal expansion and disease development.

Patients with myeloproliferative neoplasms (MPN) have high levels of inflammatory cytokines, some of which drive many of the debilitating constitutional symptoms associated with the disease and may also promote expansion of the neoplastic clone. We report here that monocytes from patients with MPN have defective negative regulation of Toll-like receptor (TLR) signaling that leads to unrestrained production of the inflammatory cytokine tumor necrosis factor α (TNF-α) after TLR activation. Specifically, monocytes of patients with MPN are insensitive to the anti-inflammatory cytokine interleukin 10 (IL-10) that negatively regulates TLR-induced TNF-α production. This inability to respond to IL-10 is a not a direct consequence of JAK2^V617F , as the phenotype of persistent TNF-α production is a feature of JAK2^V617F and wild-type monocytes alike from JAK2^V617F -positive patients. Moreover, persistent TNF-α production was also discovered in the unaffected identical twin of a patient with MPN, suggesting it could be an intrinsic feature of those predisposed to acquire MPN. This work implicates sustained TLR signaling as not only a contributor to the chronic inflammatory state of MPN patients but also a potential predisposition to acquire MPN.