High Levels of High Sensitivity-C Reactive Protein (hs-CRP) Are Associated with Older Age, Chromosomal Abnormalities and JAK2V617F Mutation with High Allele Burden in Primary Myelofibrosis (PMF)

A number of evidences indicate that inflammation and deranged innate immunity intervene in the pathobiology of PMF. In this study we aimed to analyze the inflammatory components of PMF by measuring hs-CRP in a vast population of patients. hs-CRP can detect minimal variations of serum CRP levels even in the range of normal limits, and thus is a sensitive marker of low grade systemic inflammation. We included PMF patients from the data base of the Center for the Study of Myelofibrosis in Pavia with available archived plasma. We excluded patients who had been treated with disease-modifying agents at any time before or on the date of base-cohort entry (hydroxyurea, interferon, ruxolitinib, corticosteroids) and patients with acute inflammatory or autoimmune disease, malignancy, severe liver or renal dysfunction. In this study we report the results on the determinants of levels of circulating hs-CRP in PMF in an analysis in which we used parameters that could be hypothesized with a biological plausibility to influence the level of hs-CRP. Selected predictors were: age, sex, the five different genotypes reflecting the presence or absence of the driver mutations (JAK2V617F with low allele burden (<50%), JAK2V617F mutation with high allele burden (≥ 50%), CALR mutations, MPL mutations, triple negative genotype), the accessory subclonal mutations in the ASXL1 and EZH2 genes, and abnormal karyotype. 152 subjects were analyzed at diagnosis, while 353 after (median time from diagnosis, 43 months, range, 4-396 months). 86 patients (17%) had increased hs-CRP (>1 mg/L). The mean age of the patients was 54.4 years. Increasing age was correlated with increasing hs-CRP (R=0.45;P<0.001). By dividing the PMF population into that younger or older than 50 years (this cut-off value was obtained from the ROC curve analysis),3.7% in the former category had increased levels of hs-CRP with respect to 27.4% in the latter (P<0.001). 227 patients were females and 279 males. There were significant differences in plasma hs-CRP between males and females (0.86 mg/L vs. 0.44 mg/L; P<0.001). While 21,5% of males had increased levels of hs-CRP, this proportion was 11.4 in females (P=0.002). There was a significant difference in plasma hs-CRP between subjects with different PMF genotypes (Figure). This was due to an exceedingly higher hs-CRP in patients bearing JAK2V617F mutation with high allele burden (N=82) with respect to those with low allele burden (N=190) (1.09 mg/L vs. 0.46 mg/L; P<0.001). By dividing the PMF population into that with high JAK2V617F allele burden and other genotypes, 29.2% in the former had increased levels of hs-CRP while it was 12.2% in the latter (P<0.001). Among patients with JAK2V617F mutation, there was a significant association between the level of hs-CRP and the allele burden (R=0.12; P=0.018). Cytogenetic characteristics at diagnosis were available in 83 patients and 32 (38.5%) of them had abnormal karyotype. There was a significant difference in hs-CRP between patients bearing a chromosomal aberration and those without (mean 0.90 mg/L vs. 0.35 mg/L P=0.003). By dividing chromosomal abnormalities in unfavorable and favorable, there was no difference in hs-CRP levels between the two groups. Assay of subclonal mutations ASXL1 and EZH2 was available in 99 patients, 8.8% of them had ASXL1 mutations and 4.4% had EZH2 mutation. No difference in hs-CRP was revealed between patients bearing or not ASXL1 or EZH2 or both. We investigated the collinearity of the variables significantly associated with hs-CRP. Age was correlated with the allele burden of JAK2V627F (R=0.18; P=<0.001) and higher age was associated with higher frequency of chromosomal abnormalities (P=0.023). At multivariable analysis, older age (P=0.009) and presence of chromosomal abnormalities (P=0.010) were identified as independently correlated variables, and were considered the best predictors of hs-CRP increase. In conclusion, our results highlighted the association between older age/ presence of chromosomal abnormalities and inflammation in PMF. These results were coherent with the hypothesis that chronic inflammation is a promotor of mutagenesis in MF (Hasselbalch HC. Leuk Res. 2013;37:214), but also that genomic instability (older age, high JAK2V617F allele burden, chromosomal abnormalities) is a determinant of inflammation.

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