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

Area of Science:

• Hematology
• Oncology
• Immunology

Background:

• Chronic inflammation is increasingly recognized as a key factor in the clonal evolution and progression of Philadelphia-negative myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV), and myelofibrosis (MF).
• Abnormalities in proinflammatory cytokines and immune gene dysregulation are prominent in MPNs, particularly in MF, suggesting a significant role for immune system imbalance.
• This inflammation is linked to increased risks of premature atherosclerosis, secondary nonhematologic and hematologic cancers, and a substantial comorbidity burden within the MPN patient population.

Purpose of the Study:

• To review the evidence supporting the classification of MPNs as inflammatory diseases.
• To explore the role of cytokines in MPN initiation and progression, framing MPNs within a human inflammation model of cancer development.
• To discuss the implications of this inflammatory model, including heightened risks for second cancers and other inflammation-mediated conditions, and to advocate for revised therapeutic strategies.

Main Methods:

• This review synthesizes existing evidence from preclinical and clinical studies.
• It analyzes the association between chronic inflammation, cytokine dysregulation, and disease progression in MPNs.
• The review examines the link between MPNs and inflammation-mediated comorbidities, including atherosclerosis and secondary malignancies.

Main Results:

• Evidence strongly suggests that chronic inflammation is a significant driver of clonal evolution and disease progression in MPNs.
• MPNs are associated with a notable burden of inflammation-mediated comorbidities, such as premature atherosclerosis and an elevated risk of secondary cancers.
• Cytokine dysregulation plays a crucial role in the initiation and advancement of these hematologic malignancies.

Conclusions:

• MPNs should be considered inflammatory diseases, necessitating a reevaluation of current therapeutic approaches.
• The increased risk of secondary cancers and other comorbidities underscores the systemic inflammatory nature of MPNs.
• Future therapeutic strategies should focus on early intervention, potentially combining interferon-alpha2 with anti-inflammatory agents like JAK-inhibitors to target minimal residual disease and inflammation.