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Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms
Daniel Arthur Corpuz Fisher1, Jared Scott Fowles1, Amy Zhou1
1Divisions of Hematology & Oncology, School of Medicine, Washington University in St. Louis, Saint Louis, MO, United States.
Frontiers in Immunology
|June 18, 2021
Summary
Myeloid neoplasms like MPNs involve inflammatory cytokines that drive disease progression and transformation. Targeting these inflammatory pathways offers a promising therapeutic strategy for better treatment outcomes.
Area of Science:
- Hematology
- Oncology
- Immunology
Background:
- Myeloid neoplasms, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), are characterized by clonal dominance and bone marrow niche remodeling.
- Inflammatory signaling and cytokine overproduction are hypothesized to drive malignant hematopoiesis and disease progression in these conditions.
- In Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), inflammatory cytokines contribute to the transformation of polycythemia vera (PV) and essential thrombocythemia (ET) into myelofibrosis (MF).
Purpose of the Study:
- To explore the role of inflammatory cytokines in the pathophysiology of myeloid neoplasms, particularly MPNs.
- To investigate the contribution of cytokine signaling to disease progression, transformation, and bone marrow failure.
- To identify potential therapeutic strategies targeting inflammatory pathways in MPNs.
Main Methods:
- Review of existing literature on inflammatory signaling and cytokine profiles in MPNs, including PV, ET, and MF.
- Analysis of the role of specific cytokines like TGF-β, IL-8/CXCL8, and TNFα in disease pathogenesis.
- Examination of evidence for NFκB pathway hyperactivation in MPNs and its implications for pan-hematopoietic involvement.
Main Results:
- Elevated cytokine levels are observed in MPNs, exceeding those in normal aging, and are associated with cellular signaling abnormalities.
- Cytokines contribute to MF development, extramedullary hematopoiesis, and bone marrow failure.
- Elevated IL-8/CXCL8 predicts transformation risk of MF to secondary AML (sAML); TNFα may drive clonal dominance.
Conclusions:
- MPNs are pan-hematopoietic diseases where the bone marrow microenvironment is remodeled to favor malignant clone persistence.
- Current therapies like JAK2 inhibition show limitations in reducing clonal burden and cytokine elevations, suggesting alternative strategies.
- Targeting cytokine-mediated signaling represents a promising therapeutic avenue for developing more effective treatments for MPNs.
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