Anti-inflammatory treatment in MPN: targeting TNFR1 and TNFR2 in JAK2-V617F-induced disease

Chronic nonresolving inflammatory syndrome is a major disease feature in myeloproliferative neoplasms (MPNs). Systemic inflammation promotes the growth of the JAK2-V617F1 hematopoietic stem cell clone and is associated with constitutive symptoms (eg, fever, cachexia, and fatigue). Therefore, it is being discussed whether antiinflammatory therapy, in addition to the well-established JAK inhibitor therapy, may be beneficial in the control of constitutive symptoms. Moreover, effective control of the inflammatory microenvironment may contribute to prevent transformation into secondary myelofibrosis and acute leukemia. Given the pivotal role of tumor necrosis factor a (TNF-a) in MPN and the distinct roles of TNF-a receptor 1 (TNFR1) and TNFR2 in inflammation, we investigated the therapeutic effects of aTNFR1 and aTNFR2 antibody treatment in MPN-like disease using the JAK21/VF knock-in mouse model. Peripheral blood counts, bone marrow/spleen histopathology, and inflammatory cytokine levels in serum were investigated. aTNFR2 antibody treatment decreased white blood cells and modulated the serum levels of several cytokines [CXCL2, CXCL5, interleukin-12(p40)], as well as of macrophage colony-stimulating factor, but they lacked efficacy to ameliorate hematocrit and splenomegaly. aTNFR1 antibody treatment resulted in the mild suppression of elevated hematocrit of 210.7% and attenuated splenomegaly (22% reduction in spleen weight). In conclusion, our studies show that TNFR1 and TNFR2 play different roles in the biology of JAK2-V617F-induced disease that may be of relevance in future therapeutic settings.

Automated summary

This study investigated the therapeutic effects of aTNFR1 and aTNFR2 antibody treatment in MPN-like disease induced by JAK2-V617F, showing that TNFR1 and TNFR2 play distinct roles in the biology of the disease. These findings may have relevance in future therapeutic settings.