Associations and prognostic interactions between circulating levels of hepcidin, ferritin and inflammatory cytokines in primary myelofibrosis

Abstract

Iron homeostasis is dysregulated in primary myelofibrosis (PMF), given the high prevalence of anemia, need for red blood cell (RBC) transfusions, and disease-associated inflammatory state. We measured plasma hepcidin levels in 203 consecutive PMF patients at the time of first referral; hepcidin levels were significantly higher as compared to healthy controls (P < 0.0001), and were correlated with hemoglobin of <10 g/dL, RBC transfusion requirement, serum ferritin of >500 mg/L, higher dynamic international prognostic scoring system (DIPSS)-plus risk category, the presence of circulating blasts, age of >65 years, and leukocyte count of <4 3 10 9 /L. Increased hepcidin levels predicted for inferior survival independent of six out of the eight DIPSS-plus prognostic parameters (hazard ratio [HR] 5 1.8; P 5 0.02), but not when RBC transfusion requirement, hemoglobin of <10 g/dL, or increased serum ferritin were included in the Cox model. Multivariable analysis that considered the four overlapping prognostic variables revealed that increased hepcidin (HR 5 1.9; P 5 0.03) and increased ferritin (HR 5 2.3; P 5 0.04), but not hemoglobin of <10 g/dL or RBC transfusion requirement, independently retained their significance for predicting survival. Accordingly, increased levels of both hepcidin and serum ferritin (seen in 29% of patients) predicted inferior survival independent of DIPSS-plus or increased inflammatory cytokine levels (HR 5 2.4; P 5 0.002), and could be considered in future prognostic models for PMF. Am. J.

JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis

“…34 These changes in iron metabolism were more pronounced in JAK2;Ex12 mice than in our JAK2-V617F mice, and may contribute to the more prominent erythrocytosis observed in JAK2;Ex12 mice compared with JAK2-V617F mice. In line with a previous report, 38 serum hepcidin levels were significantly elevated in PMF patients with JAK2-V617F ( Figure 7H). Consistently, a trend toward increased TFR1 and ERFE mRNA expression was also noted in BFU-E Hepcidin protein concentration in the serum of PV patients with JAK2 exon 12 mutations (n 5 6) and in MPN patients with the JAK2-V617F mutation (PV, n 5 10; ET, n 5 12; and PMF, n 5 10 patients per group).…”

Diagnosis of iron-deficient states

“…It is still unclear how the determination of serum hepcidin would fit into diagnostic algorithms for iron deficient states outside of IRIDA 88 . With the exception of hereditary hemochromatosis, in which elevated serum ferritin is accompanied by inappropriately low serum hepcidin, in most other cases serum ferritin and hepcidin levels correlate with each other.…”

Increased plasma nicotinamide phosphoribosyltransferase is associated with a hyperproliferative phenotype and restrains disease progression in MPN‐associated myelofibrosis

“…However, the molecular mechanisms underlying MPN-associated myelofibrosis are still not clear. JAK-STAT pathway activation is the main mechanism of myeloproliferation [3,4]; however, available evidence indicates that inflammatory/immune mechanisms play an important role in the phenotype of MPN-associated myelofibrosis by increased production of inflammatory cytokines and reduced number of regulatory T-cells [5][6][7][8][9][10]. From these considerations, it appears that understanding the mechanisms involved in the initiation and progression of MPNassociated myelofibrosis is a pivotal step for the generation of more effective therapeutic approaches.…”