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.

Figures

Figure 1

Progression from chronic inflammation to solid and blood cancers. A physical, chemical, or infectious injury leads to tissue and cell damage and activation of antiapoptosis signaling pathways in affected cells, which results in the autocrine and paracrine production and consumption of prosurvival, inflammatory cytokines, as well as chemokines, to attract immune cells of the lymphoid and myeloid lineages to the site of injury. Over time, established inflammation (chronic inflammation) constantly overstimulates the production of hematopoietic cells and induces more tissue and cell damage, hereby increasing the rate of DNA duplication and risk of defective DNA reparation and mutation, both in cells from affected tissues (increased risk of solid cancer) and in lymphoid and myeloid cells participating in the immune/inflammatory response (increased risk of hematological malignancy).

Figure 2

Increased risk of myeloid malignancy in case of chronic inflammation. Chronic inflammation may be related to solid cancer or to other causes (infectious, toxic, and physical). In all cases the immune response includes an increased stimulation of the production of myeloid cells, with the associated increased risk of DNA alteration in dividing progenitor cells. Over the years, a myeloid progenitor may acquire a defect in a gene critical for survival or proliferation (MPL, JAK2, and CALR?) and a MPL-, JAK2-, or CALR-mutated malignant clone may expand and lead to a MPN. Other mutations providing a mild growth advantage (TET2, IDH1/2?) may occur before or after the MPL, JAK2, or CALR mutations. In the case of inflammation related to solid cancer, cancer cells and the inflammatory cytokines they produce likely affect immune cells.

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.

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.

Figure 5

Chronic inflammation in myeloid neoplasms and new therapeutic options. In MPN patients, chronic inflammation includes the participation of JAK2-V617F-, MPL-W515 L/K-, or CALR-mutated cells and the production of inflammation cytokines under the control of these mutations. Chronic inflammation may also be reactive to the MPN clone or to other coexisting causes of inflammation (hypoxia due to cell accumulation in the bone marrow; thrombosis; infection; others). Healthy and mutated (clonal) myeloid cells participate in MPN-associated reactive inflammation, and the NF-κB, JAK/STAT, and HIF pathways are chronically activated in the MPN clone and in cells from the bone marrow environment. Ideally treatment should combine the following: (1) inhibition of the JAK2-V617F, MPL-W515L/K, or CALR mutations, possible with JAK inhibitors; (2) inhibition of chronic inflammation, via the neutralization or inhibition of inflammation cytokines or receptors, and/or the inhibition of the NF-κB and HIF pathways; (3) in cases where chronic inflammation precedes mutation, and a cause is identified, adequate treatment of the initial cause of inflammation could be added (e.g., antibiotics or antiviral treatment in case of latent infection).