Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation

Figure 3

Main molecular pathways activated for the production of inflammatory cytokines. Three main transcription factors control the production of inflammatory cytokines and subsequently cell survival and proliferation: (i) HIF-1α, activated in hypoxic tissues, regulates the transcription of multiple genes including numerous inflammatory cytokines and growth factors that promote cell survival, fibrosis, and neoangiogenesis [12, 13]; (ii) NF-κB induces the expression of many inflammation cytokines and growth factors, as well as HIF-1α mRNA; (iii) STAT1, like NF-κB, induces the expression of several inflammation cytokines. To a lesser degree, STAT3 also regulates cytokine transcription, notably of IL-6. STAT1 and STAT3 are activated by JAK kinases, essentially JAK1, but other kinases also activate STAT transcription factors (e.g., MET, the HGF receptor). In addition, cancer-associated mutations may affect the expression (TET2 and IDH1/2 mutations) or signaling (JAK2-V617F, CBL, or LNK mutations) of cytokines or cytokine receptors. Certain growth factors (TGF-β) and other molecules such as liposaccharide (LPS), a component of Gram-negative bacteria, can also activate the NF-κB pathway and subsequently the HIF and JAK/STAT pathways. Red arrows represent pathways that directly lead to increased production of inflammatory cytokines.