Inflammatory Pathophysiology as a Contributor to Myeloproliferative Neoplasms.
TLDR
In this article, inflammatory cytokines are considered to be responsible for a highly deleterious pathophysiologic process: the phenotypic transformation of polycythemia vera (PV) or essential thrombocythemia (ET), and the equivalent emergence of primary myelofibrosis (PMF).Abstract:
Myeloid neoplasms, including acute myeloid leukemia (AML), myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDS), feature clonal dominance and remodeling of the bone marrow niche in a manner that promotes malignant over non-malignant hematopoiesis. This take-over of hematopoiesis by the malignant clone is hypothesized to include hyperactivation of inflammatory signaling and overproduction of inflammatory cytokines. In the Ph-negative MPNs, inflammatory cytokines are considered to be responsible for a highly deleterious pathophysiologic process: the phenotypic transformation of polycythemia vera (PV) or essential thrombocythemia (ET) to secondary myelofibrosis (MF), and the equivalent emergence of primary myelofibrosis (PMF). Bone marrow fibrosis itself is thought to be mediated heavily by the cytokine TGF-β, and possibly other cytokines produced as a result of hyperactivated JAK2 kinase in the malignant clone. MF also features extramedullary hematopoiesis and progression to bone marrow failure, both of which may be mediated in part by responses to cytokines. In MF, elevated levels of individual cytokines in plasma are adverse prognostic indicators: elevated IL-8/CXCL8, in particular, predicts risk of transformation of MF to secondary AML (sAML). Tumor necrosis factor (TNF, also known as TNFα), may underlie malignant clonal dominance, based on results from mouse models. Human PV and ET, as well as MF, harbor overproduction of multiple cytokines, above what is observed in normal aging, which can lead to cellular signaling abnormalities separate from those directly mediated by hyperactivated JAK2 or MPL kinases. Evidence that NFκB pathway signaling is frequently hyperactivated in a pan-hematopoietic pattern in MPNs, including in cells outside the malignant clone, emphasizes that MPNs are pan-hematopoietic diseases, which remodel the bone marrow milieu to favor persistence of the malignancy. Clinical evidence that JAK2 inhibition by ruxolitinib in MF neither reliably reduces malignant clonal burden nor eliminates cytokine elevations, suggests targeting cytokine mediated signaling as a therapeutic strategy, which is being pursued in new clinical trials. Greater knowledge of inflammatory pathophysiology in MPNs can therefore contribute to the development of more effective therapy.read more
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References
More filters
Journal ArticleDOI
The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis--impact on disease phenotype
TL;DR: The JAK2 V617F tyrosine kinase mutation is present in the great majority of patients with polycythemia vera (PV), and approximately half of the patients with essential thrombocythemia and primary myelofibrosis.
Journal ArticleDOI
MPNs as Inflammatory Diseases: The Evidence, Consequences, and Perspectives
TL;DR: 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 are described.
Journal ArticleDOI
Serum interleukin (IL)-1, IL-2, sIL-2Ra, IL-6 and thrombopoietin levels in patients with chronic myeloproliferative diseases
Katerina E. Panteli,Eleftheria Hatzimichael,Paraskevi K. Bouranta,Afroditi Katsaraki,Konstantinos Seferiadis,Justin Stebbing,Konstantinos L. Bourantas +6 more
TL;DR: There was a positive correlation between IL‐2, sIL‐2Ra, IL‐6 and angiogenesis in bone marrow samples, and Cytokines may be useful markers for predicting clinical evolution, reflecting increasedAngiogenesis.
Journal ArticleDOI
Inhibition of NEDD8-Activating Enzyme Induces Rereplication and Apoptosis in Human Tumor Cells Consistent with Deregulating CDT1 Turnover
TL;DR: Data demonstrate that CDT1 accumulation mediates the DNA rereplication phenotype resulting from loss of NAE function, and represents an unprecedented opportunity to explore this mechanism of cytotoxicity for the treatment of cancer.
Journal ArticleDOI
TNF-α induces leukemic clonal evolution ex vivo in Fanconi anemia group C murine stem cells
June Li,Daniel P. Sejas,Xiaoling Zhang,Yuhui Qiu,Kalpana Nattamai,Reena Rani,Keaney Rathbun,Hartmut Geiger,Hartmut Geiger,David A. Williams,David A. Williams,Grover C. Bagby,Qishen Pang,Qishen Pang +13 more
TL;DR: TNF- α exposure creates an environment in which somatically mutated preleukemic stem cell clones are selected and from which unaltered TNF-α–hypersensitive Fancc–/– stem cells are purged.