Figure 8.

JAK2V617F-dependent vs. mutation-independent inflammation in MPNs. At least 26 cytokines are overproduced in MPNs. CALR mutants did not alter cytokine production, whereas JAKV617F increased the expression of IL-1Rα, IL-1β and IP-10. Other cytokines overexpressed in MPNs are presumably produced by nonmutated cells, and this type of inflammation is likely to precede the acquisition of JAK2/STAT5 activating mutations. An autoimmune response to GlcSph, observed in 20% of MPNs, could be an early cause of chronic inflammation—and excessive IL-1β production—eventually leading to the acquisition of JAK2 or CALR mutations and MPN development. In JAK2V617F-mutated MPNs, strongly inflammatory IL-1β associated with IL-1Rα expression, both induced by JAK2V617F, further stimulate cytokine production by both nonmutated cells of the bone marrow environment and mutated cells. JAK2V617F-mutated cells also secrete TNF-α, known to enhance clonal expansion. Neither IL-1β nor TNF-α signal via JAK/STAT, and thus are not sensitive to JAK inhibitors. In contrast, IFN-α represses IL-1β, and also HGF, an autocrine survival factor for clonal MPN progenitors. In addition, IFN-α stimulates T-lymphocyte subsets that secrete anti-inflammatory IL-4, and two prothrombopoiesis and prothrombosis cytokines—IL-9 (an inducer of IL-4) and IL-17.