Defective negative regulation of Toll-like receptor signaling leads to excessive TNF-α in myeloproliferative neoplasm

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. Wereport 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 a (TNF-alpha) 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-alpha production. This inability to respond to IL-10 is a not a direct consequence of JAK2(V617F), as the phenotype of persistent TNF-alpha production is a feature of JAK2(V617F) and wild-type monocytes alike from JAK2(V617F)-positive patients. Moreover, persistent TNF-alpha 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.