TNFα is not required for development of MPN but promotes expansion of JAK2^V617F cells in a murine transplantation model. Bone marrow from 5-FU treated TNFα^+/+ (C57B/6) or TNFα^−/− (B6.129S-Tnf^tm1Gkl/J) mice was infected with JAK2^V617F retrovirus by spinoculation and injected into syngeneic lethally irradiated hosts (n = 5 for each group). (A) Percentage of GFP⁺ cells in peripheral blood (B) spleen and liver weights at time of sacrifice, (C) percentages of GFP⁺ cells in bone marrow and spleen at time of sacrifice, and (D) H&E-stained histologic sections of representative TNFα^+/+ and TNFα^−/− bone marrow, spleen, and liver. Large panels represent 10× magnification, panel inserts represent 40× magnification of the same area. Images were captured with a Leica DC300 camera running IM50 Image Manager Version 5 software. (E) Model of TNFα-induced JAK2^V617F clonal evolution in MPN. In a TNFα-sensitive stem cell pool JAK2^V617F induced TNF resistance provides a strong selective advantage, allowing for the expansion of the mutant clone and development of clinical disease. Maintenance of a high TNFα environment by JAK2^V617F cells further enhances the selective advantage for the JAK2^V617F clone.