Pathogenesis of Myeloproliferative Neoplasms: Role and Mechanisms of Chronic Inflammation

Abstract

Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal diseases characterized by the excessive and chronic production of mature cells from one or several of the myeloid lineages. Recent advances in the biology of MPNs have greatly facilitated their molecular diagnosis since most patients present with mutation(s) in the JAK2, MPL, or CALR genes. Yet the roles played by these mutations in the pathogenesis and main complications of the different subtypes of MPNs are not fully elucidated. Importantly, chronic inflammation has long been associated with MPN disease and some of the symptoms and complications can be linked to inflammation. Moreover, the JAK inhibitor clinical trials showed that the reduction of symptoms linked to inflammation was beneficial to patients even in the absence of significant decrease in the JAK2-V617F mutant load. These observations suggested that part of the inflammation observed in patients with JAK2-mutated MPNs may not be the consequence of JAK2 mutation. The aim of this paper is to review the different aspects of inflammation in MPNs, the molecular mechanisms involved, the role of specific genetic defects, and the evidence that increased production of certain cytokines depends or not on MPN-associated mutations, and to discuss possible nongenetic causes of inflammation.

Bridging blood cancers and inflammation: The reduced Cancitis model

“…Thus the hematopoietic steady state is stable until the co-existing steady state takes over while the leukemic steady state remains unstable. Inflammation is presumably another important quantity for the onset and development of blood cancer, greatly influenced by the inflammatory stimulation J [19,10,39,33,31,30,71,72,2,29]. This suggests that the body may manage initial leukemia as long as the self-renewal rate is not too high, but fails to manage it if an inflammation appears.…”

“…This reflects the fact that an increase in hematopoietic cell death instigates the birth of extra cells. Finally, the stem cells may mutate with a mutation rate r m , which is believed to increase with inflammation [19,10,39,33,31,30,70,68,71,72,2,29].…”

Carotid artery stiffness, digital endothelial function, and coronary calcium in patients with essential thrombocytosis, free of overt atherosclerotic disease

“…However, the association of JAK2 positive status and markers of inflammation has been firmly established 2,4-7,9 and all our patients with ET were JAK2 positive.…”

Myeloproliferative neoplasms (MPNs) – Part 2: A nursing guide to managing the symptom burden of MPNs

“…They also appear to be related to the production of pro-inflammatory cytokines that disrupt neurohormonal signalling and impair neurotransmitter production . Other common MPN-associated symptoms, such as fever, night sweats and weight loss, are also related to the release of pro-inflammatory cytokines during the disease process (Geyer et al, 2015;Hermouet et al, 2015). Treatment with ruxolitinib has been shown to improve these constitutional symptoms compared to standard therapy or placebo (Vannucchi et al, 2015;Mesa et al, 2013;Verstovesk et al, 2012).…”