Summary
Background
Cell division cycle 25c (
CDC25c
) is a gene coding a phosphatase controlling entry into mitosis upon activation through Polo-like kinase 1 (PLK1) and serves as a key regulator of ...cell division. The
CDC25c
was reported to be dysregulated in some malignant diseases, but its role in myelofibrosis has not yet been elucidated.
Methods
We have retrospectively investigated
CDC25c
mRNA expression in bone marrow aspirates of 43 patients with myelofibrosis (28 primary PMF and 15 secondary myelofibrosis SMF) and 12 controls.
Results
CDC25c
mRNA expression did not significantly differ between PMF, SMF and controls (median ∆CT 3.08 vs 2.86 vs 2.29 for PMF, SMF and controls, respectively;
P
= 0.162). Patients presenting with higher
CDC25c
mRNA expression were of older age (
P
= 0.037), had statistically significantly higher white-blood-cells (
P
= 0.017), larger liver size (
P
= 0.022), higher absolute neutrophil (
P
= 0.010), monocyte (
P
= 0.050), basophil (
P
= 0.012), and eosinophil counts (
P
= 0.013). Patients presenting with high
CDC25c
mRNA expression had statistically significantly inferior overall survival compared to low
CDC25c
expression group (HR = 2.99;
P
= 0.049). Median overall survival was not reached in patients with low and was 44 months in patients with high
CDC25c
expression.
Conclusion
Our data suggest that higher
CDC25c
expression is associated with more proliferative phenotype of myelofibrosis and is prognostic of worse survival. Future studies investigating these interesting associations are warranted.
Summary
Background
Serum uric acid (SUA) can promote inflammation and is associated with increased cardiovascular morbidity. Primary (PMF) and secondary myelofibrosis (SMF) are myeloproliferative ...neoplasms characterized by high cellular turnover and substantial risk of thrombosis and death.
Methods
We have retrospectively investigated SUA in 173 patients with myelofibrosis (125 PMF; 48 SMF) and 30 controls.
Results
The PMF patients had significantly higher SUA in comparison to SMF and controls. In both PMF and SMF higher SUA was significantly associated with arterial hypertension and decreased renal function. Among PMF patients, higher SUA was significantly associated with older age, larger spleen, higher white blood cell counts, higher lactate dehydrogenase, lower immunoglobulin G levels, allopurinol use and non-smoking. Among SMF patients, higher SUA was associated with male sex (
P
< 0.05 for all analyses).
In PMF higher SUA was univariately associated with inferior survival (> 427 μmol/L hazard ratio (HR) = 2.22;
P
= 0.006) and shorter time to thrombosis (> 444 μmol/L HR = 5.05;
P
= 0.006), which could be shown separately for arterial (> 380 μmol/L; HR = 4.9;
P
= 0.013) and venous thromboses (> 530 μmol/L; HR = 17.9;
P
< 0.001). In multivariate analyses, SUA remained significantly associated with inferior survival independent of the Dynamic International Prognostic Staging System and with shorter time to thrombosis independent of age in PMF patients; however, the prognostic significance of SUA was diminished after including serum creatinine in the models. SUA was not prognostic in SMF patients.
Conclusion
The PMF patients present with higher SUA levels, which are associated with features of more advanced disease and higher risks of arterial and venous thrombosis and death.
Blood plasma represents a large reservoir of cytokines and other mediators of inflammation. Higher estimated plasma volume status (ePVS) has been shown to correlate with increased thrombotic risk in ...polycythemia vera patients, but its clinical and prognostic associations in patients with myelofibrosis are unknown which we aim to evaluate in this study.
We retrospectively analysed a multicentric cohort of 238 patients with primary (PMF) and secondary myelofibrosis (SMF). Estimated plasma volume status was calculated using the Strauss-derived Duarte formula. Overall survival (OS) and time to thrombosis (TTT) considering both arterial and venous thromboses were primary endpoints of interest.
Median ePVS was 5.8 dL/g and it did not significantly differ between PMF and SMF patients. Patients with more advanced disease features, more pronounced inflammation and higher comorbidity burden had higher ePVS. Higher ePVS (> 5.6 dL/g) was associated with shorter OS in PMF (unadjusted hazard ratio, HR = 2.8, 95% confidence interval, CI (1.79-4.41), P < 0.001) and SMF (unadjusted HR = 2.55, 95% CI (1.1-5.71), P =0.025) and with shorter TTT in PMF (> 7 dL/g, unadjusted HR = 4.1, 95% CI (1.44-11.59), P = 0.009) patients. Associations with OS diminished in multivariate analyses after adjustments for the dynamic-international-prognostic-scoring-system (DIPSS) and myelofibrosis-secondary-to-PV-and ET-prognostic-model (MYSEC-PM), respectively. Association with TTT remained significant independently of JAK2 mutation, white blood cell count and chronic kidney disease.
Myelofibrosis patients with more advanced disease features and more pronounced inflammation have higher ePVS, indicative of expanded plasma volume. Higher ePVS is associated with impaired survival in PMF and SMF and higher thrombotic risk in PMF patients.
We retrospectively investigated C reactive protein to albumin ratio (CAR) in a cohort of 142 patients with myelofibrosis 101 primary (PMF); 41 secondary (SMF) and compared it to hematological and ...clinical parameters. Among other associations, higher CAR was significantly associated with higher grade of bone marrow fibrosis, lower frequency of Calreticulin (CALR) mutations, presence of constitutional symptoms, massive splenomegaly, transfusion dependency, blast phase disease, lower hemoglobin, lower platelets, higher ferritin and higher lactate dehydrogenase (LDH) (p < .05 for all analyses). Higher CAR was able to predict inferior survival in PMF independently of DIPSS hazard ratio (HR)=2.17; p = .015 for high CAR and HR = 2.05; p < .001 for DIPSS and in SMF independently of Mysec-PM (HR = 6.48; p = .022 for high CAR and HR = 2.63; p = .013 for Mysec-PM) demonstrating its good prognostic potential. CAR seems to be an independent and prognostically relevant parameter, both in PMF and SMF, and might aid in timely recognition of most vulnerable patients.
Blood plasma experiences substantial changes in both volume and composition in patients with chronic myeloproliferative neoplasms (MPN) and represents a large reservoir of cytokines and other ...mediators of inflammation. Higher estimated plasma volume status (ePVS) has recently been shown to correlate with increased thrombotic risk in polycythemia vera patients.
To estimate clinical and prognostic associations of ePVS in patients with myelofibrosis.
Retrospective cohort study.
6 hematology centers.
238 myelofibrosis patients, 168 with PMF, 34 with post-PV SMF and 36 with post-ET SMF.
ePVS was calculated using the Strauss derived Duarte formula: (100-hematocrit (%)/hemoglobin (g/dL) and expressed as dl/g.
Overall survival (OS) and time to thrombosis (TTT).
Median ePVS was 5.8 dl/g and it did not significantly differ between PMF and SMF patients. Among other associations, higher ePVS was significantly associated with higher degree of bone-marrow fibrosis, absence of JAK2-mutation, lower white blood cells (WBC), platelets and hemoglobin, presence of circulatory blasts, higher C-reactive protein, higher lactate dehydrogenase, lower albumin and higher Charlson comorbidity index in an overall cohort, as well as with more pronounced splenomegaly and higher Dynamic International Prognostic Scoring System (DIPSS) risk in primary myelofibrosis (PMF) and higher Mysec-PM risk in secondary myelofibrosis (SMF) patients (P<0.05 for all analyses). Higher ePVS (>5.6 dl/g) was associated with shorter overall-survival (OS) in PMF (HR=2.8, P<0.001) and SMF (HR=2.55, P=0.025) and with shorter time-to-thrombosis in PMF (>7 dl/g, HR=4.1, P=0.009) patients. Associations with overall survival diminished in multivariate analyses after adjustments for DIPSS and Mysec-PM, respectively. Association with TTT remained significant independently of JAK2, WBC and chronic kidney disease.
Myelofibrosis patients with more advanced disease features and more pronounced inflammation have higher ePVS, indicative of expanded plasma volume. Higher ePVS is associated with impaired survival in PMF and SMF and higher thrombotic risk in PMF patients.
Aurora-kinase-A (AURKA), BORA and Polo-like-kinase-1 (PLK1) are regulating cell-cycle control and promotion of mitosis entry. AURKA contributes to Janus-kinase-2 (JAK2) activation and increased AURKA ...protein levels were reported in CD34+ and CD41+ cells of myeloproliferative neoplasm patients, leading to aneuploidy and aberrant megakaryopoiesis. We aimed to investigate AURKA, BORA and PLK1 mRNA expression in unfractionated bone-marrow aspirates of 43 patients with myelofibrosis (28 primary-/PMF, 15 secondary-myelofibrosis/SMF) and 12 controls and to assess their clinical correlations. AURKA expression did not significantly differ between myelofibrosis and controls (P = 0.466). Higher AURKA expression was significantly associated with higher absolute monocyte-count (P = 0.024) and shorter overall survival (HR = 3.77; P = 0.012). Patients with both PMF and SMF had lower BORA expression than controls (P = 0.009). Higher BORA expression was significantly associated with absence of constitutional symptoms (P = 0.049), absence of circulatory blasts (P = 0.047), higher monocyte- (P = 0.040) and higher eosinophil-counts (P = 0.016) and had neutral effect on survival (P > 0.05). PLK1 expression did not significantly differ between myelofibrosis and controls (P = 0.103). Higher PLK1 expression was significantly associated with higher white-blood-cell-count (P = 0.042) and inferior overall survival (HR = 5.87; P = 0.003). In conclusion, AURKA, BORA and PLK1 are involved in pathogenesis of myelofibrosis and may affect survival. Future studies investigating these interesting associations are warranted.
•Higher PLK1 and AURKA expression bear worse prognosis•BORA expression was downregulated in myelofibrosis•AURKA-BORA-PLK1 axis deserves to be further investigated in myelofibrosis
