Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
, 2015, 102476

MPNs as Inflammatory Diseases: The Evidence, Consequences, and Perspectives

Affiliations
Review

MPNs as Inflammatory Diseases: The Evidence, Consequences, and Perspectives

Hans Carl Hasselbalch et al. Mediators Inflamm.

Abstract

In recent years the evidence is increasing that chronic inflammation may be an important driving force for clonal evolution and disease progression in the Philadelphia-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF). Abnormal expression and activity of a number of proinflammatory cytokines are associated with MPNs, in particular MF, in which immune dysregulation is pronounced as evidenced by dysregulation of several immune and inflammation genes. In addition, chronic inflammation has been suggested to contribute to the development of premature atherosclerosis and may drive the development of other cancers in MPNs, both nonhematologic and hematologic. The MPN population has a substantial inflammation-mediated comorbidity burden. This review describes the evidence for considering the MPNs as inflammatory diseases, A Human Inflammation Model of Cancer Development, and the role of cytokines in disease initiation and progression. The consequences of this model are discussed, including the increased risk of second cancers and other inflammation-mediated diseases, emphasizing the urgent need for rethinking our therapeutic approach. Early intervention with interferon-alpha2, which as monotherapy has been shown to be able to induce minimal residual disease, in combination with potent anti-inflammatory agents such as JAK-inhibitors is foreseen as the most promising new treatment modality in the years to come.

Figures

Figure 1
Figure 1
Vicious cycle of inflammation in the biological continuum of ET, PV, and MF. Chronic inflammation is proposed as the trigger and driver of clonal evolution in the biologic continuum from early disease state (ET/PV) to a more advanced disease state (MF). It is possible that combination therapy, using low doses of agents such as interferon-alpha, Janus kinase inhibitors, and statins at the early disease stage, will positively influence the vicious cycle of disease progression. HGF: hepatocyte growth factor; IL: interleukin; MPN: myeloproliferative neoplasm; and TNF: tumor necrosis factor.
Figure 2
Figure 2
Patients with MPNs have a massive cardiovascular and thromboembolic disease burden.
Figure 3
Figure 3
Chronic inflammation as the driving force for clonal evolution in MPNs. Tumor burden and comorbidity burden are illustrated for patients with JAK2V617F positive MPNs. Comorbidity burden increases from early disease stage (ET/PV) to the accelerated phase with myelofibrotic and leukemic transformation. With permission: H. C. Hasselbalch [12]. AML: acute myeloid leukemia; ET: essential thrombocythemia; JAK: Janus kinase; PPV-MF: post-polycythemia vera; and PV: polycythemia vera.
Figure 4
Figure 4
Patients with MPNs have an increased risk of second cancer not only after the MPNs diagnosis but also in the pre-MPNs diagnosis phase, which may last several years in which the patients are at an increased risk of severe cardiovascular and thromboembolic events. According to this model, the initial stem cell insult has occurred 5–10–15 years before the MPNs diagnosis.
Figure 5
Figure 5
Inflammation in the circulation elicits in vivo leukocyte and platelet aggregation giving rise to circulating microaggregates with ensuing impairment of microcirculation, tissue ischemia, and ultimately development of ulcers on toes and fingers which may terminate with gangrene. Treatment with aspirin momentarily resolves microaggregation with improvement in microcirculation.
Figure 6
Figure 6
The MPNs care pathway and the effect of early intervention. It is suggested that ET, PV, and MF form a biological continuum and, thus, early intervention with combination therapies including JAK1/2 inhibitors, IFN, and/or statins is likely to result in the inhibition of disease evolution. ASCT: allogeneic stem cell transplantation; ET: essential thrombocythemia; HU: hydroxyurea; IFN: interferon; JAK: Janus kinase; MF: myelofibrosis; and PV: polycythemia vera (with permission: H. C. Hasselbalch [12]).

Similar articles

See all similar articles

Cited by 28 articles

See all "Cited by" articles

References

    1. Campbell P. J., Green A. R. The myeloproliferative disorders. The New England Journal of Medicine. 2006;355(23):2452–2466. doi: 10.1056/nejmra063728. - DOI - PubMed
    1. Kristinsson S. Y., Landgren O., Samuelsson J., Björkholm M., Goldin L. R. Autoimmunity and the risk of myeloproliferative neoplasms. Haematologica. 2010;95(7):1216–1220. doi: 10.3324/haematol.2009.020412. - DOI - PMC - PubMed
    1. Frederiksen H., Farkas D. K., Christiansen C. F., Hasselbalch H. C., Sørensen H. T. Chronic myeloproliferative neoplasms and subsequent cancer risk: a Danish population-based cohort study. Blood. 2011;118(25):6515–6520. doi: 10.1182/blood-2011-04-348755. - DOI - PubMed
    1. Marchioli R., Finazzi G., Landolfi R., et al. Vascular and neoplastic risk in a large cohort of patients with polycythemia vera. Journal of Clinical Oncology. 2005;23(10):2224–2232. doi: 10.1200/jco.2005.07.062. - DOI - PubMed
    1. Hasselbalch H. Idiopathic myelofibrosis: a clinical study of 80 patients. American Journal of Hematology. 1990;34(4):291–300. doi: 10.1002/ajh.2830340411. - DOI - PubMed

MeSH terms

LinkOut - more resources

Feedback