Mediators of Inflammation / 2015 / Article / Fig 4

Review Article

Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation

Figure 4

Molecular pathways activated by inflammatory cytokines and growth factors and affected by MPN-associated mutations. Most cytokine and growth factor receptors can activate the HIF-1α, NF-κB, and/or one or more of the different JAK/STAT pathways, either directly or indirectly. Among the JAK kinases, myeloid cells express essentially JAK2 and to a lesser degree JAK1 and TYK2 (not represented). JAK2 activates STAT5 and STAT3. JAK1 activates mainly STAT1 and to a lesser degree STAT3. The different STAT transcription factors form homodimers as well as heterodimers, which allows for a differential regulation of the expression of inflammatory cytokines. In MPN clonal cells, the JAK2-coupled receptors of EPO, TPO, and G-CSF may form complexes with and activate wild type JAK2 only, V617F-mutated JAK2 only, or wild type and V617F-mutated JAK2, which likely result in different levels of activation of the JAK2/STAT pathways concerned. Moreover, EPO, TPO, and G-CSF activate other molecular pathways besides the JAK/STAT pathways, such as the antiapoptosis, prosurvival PI3K/AKT pathway and the proproliferation RAS/MAPK pathway. Of note, activation of HIF-1α leads to an increased production of inflammatory cytokines in all cell types, but HIF-1α induces EPO expression only in the rare EPO-producing cell types (renal cells, neuronal cells, and certain tumors). LNK loss-of-function mutants result in enhanced activation of JAK2/STAT5. The CBL mutants detected in MPNs also enhance JAK/STAT signaling. Blue arrows represent JAK/STAT pathways, and red arrows represent HIF pathways.

We are committed to sharing findings related to COVID-19 as quickly as possible. We will be providing unlimited waivers of publication charges for accepted research articles as well as case reports and case series related to COVID-19. Review articles are excluded from this waiver policy. Sign up here as a reviewer to help fast-track new submissions.