NF-κB is a key regulator of inflammation and the immune activation against pathogens. On the other hand, constitutive and dysregulated NF-κB activation has been shown to lead to hematologic malignancies. Thus, NF-κB activity has to be properly regulated to achieve this delicate balance. Recent studies on microRNA-146a (miR-146a) suggest it to be an important negative regulator of NF-κB activation by targeting TRAF6 and IRAK1. To characterize the function of miR-146a in the context of NF-κB activation in the hematopoietic system, we have created a knockout (KO) mouse with germline deletion of miR-146a gene. We have shown that over time miR-146a KO mice develop a myeloproliferative condition in spleen and bone marrow that progresses to splenic myeloid sarcoma and bone marrow fibrosis. The myeloproliferative disease is driven by dysregulated NF-κB activation as the KO spleen and bone marrow cells show increased NF-κB activity and reduction in NF-κB level effectively rescues the myeloproliferative disease. In addition, the KO mice exhibit a chronic inflammatory state with increased cytokine production and macrophages from the KO are hyper-activated upon primary LPS stimulation and secondary re-stimulation. In this study, we have provided genetic evidence that miR-146a functions as a tumor suppressor in the hematopoietic system and highlighted the important role of miR-146a as a negative regulator of NF-κB activation and inflammation.
Taganov:Regulus Therapeutics Inc: Employment.
Asterisk with author names denotes non-ASH members.