Aurora kinase A / Polo-like kinase 1 signaling pathway analysis in patients with myelofibrosis

Aurora kinaza A (AURKA), protein Aurora borealis (BORA), Polo-like kinaza 1 (PLK1) i Cell-division-cycle 25c (CDC25c) kontroliraju stanični ciklus i ulazak stanice u mitozu, a njihova disregulacija opisana je u brojnim malignim bolestima. Cilj rada bio je ispitati do sad nedovoljno istražen izražaj njihovih mRNA u mijeloproliferativnoj bolesti, mijelofibrozi (MF). Iz citoloških punktata koštane srži urađena je PCR mRNA analiza navedenih gena u 43 bolesnika s mijelofibrozom, i to 28 s primarnom (PMF) i 15 sa sekundarnom mijelofibrozom (SMF). U kontrolnim skupinama bilo je 12 ispitanika s agresivnim ne-Hodgkinovim limfom bez infiltracije koštane srži i 6 ispitanika s reaktivnom promjenom koštane srži bez zloćudne bolesti. Optimalne granične vrijednosti izražaja mRNA za diskriminaciju preživljenja odabrane su korištenjem analize ROC krivulje. Nije bilo značajne razlike u izražaju AURKA mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.466). Viša vrijednost izražaja AURKA mRNA značajno je povezana s većim apsolutnim brojem monocita (P=0.024) i kraćim ukupnim preživljenjem (HR=3.77; P=0.012). U bolesnika s PMF i SMF značajno je niži izražaj BORA mRNA u odnosu na kontrolne ispitanike (P=0.009). Viša vrijednost izražaja BORA mRNA značajno je povezana s povoljnim prognostičkim pokazateljima: odsutnošću konstitucijskih simptoma (P=0.049) i cirkulirajućih blasta (P=0.047), ali bez značajne povezanosti s ukupnim preživljenjem (P>0.05). Nije bilo značajne razlike u izražaju PLK1 mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.103). Viša vrijednost izražaja PLK1 mRNA značajno je povezana s većim ukupnim brojem leukocita (P=0.042) i kraćim ukupnim preživljenjem (HR=5.87; P=0.003). Nije bilo značajne razlike u izražaju CDC25c mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.162). Viša vrijednost izražaja CDC25c mRNA značajno je povezana s nepovoljnim prognostičkim pokazateljima: većom jetrom (P=0.022), većim ukupnim brojem leukocita (P=0.017), većim apsolutnim brojem neutrofila (P=0.010), monocita (P=0.050), bazofila (P=0.012) i eozinofila (P=0.013) te kraćim ukupnim preživljenjem (HR=2.99; P=0.049). Izražaj ovih gena ima utjecaj na ukupno preživljenje u mijelofibrozi te istraživanje treba proširiti na druge hematološke zloćudne bolesti i one s reaktivnim i prolaznim promjenama hematopoeze.Aurora kinase A (AURKA), Aurora borealis protein (BORA), Polo-like kinase 1 (PLK1) and Cell-division-cycle 25c (CDC25c) are required for cell cycle control and promotion of mitosis entry. Their dysregulation has been described in a number of malignant diseases. However, their role in pathogenesis of myelofibrosis is less known. We investigated AURKA, BORA, PLK1 and CDC25c mRNA expression in bone marrow aspirates of 43 patients with myelofibrosis (28 primary - PMF, 15 secondary myelofibrosis - SMF) and 18 controls (the first control group of 12 with limited stage of aggressive non Hodgkin lymphoma without bone marrow involvement and the second group of 6 with nonmalignant reactive bone marrow). Optimal cut-off values for dichotomization of expression levels of investigated genes for the purpose of survival analysis were done using the ROC curve analysis with survival status as a classification variable. AURKA mRNA 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 mRNA expression than controls (P=0.009). Higher BORA expression was significantly associated with favourable prognostic factors: absence of constitutional symptoms (P=0.049) and absence of circulatory blasts (P=0.047), but with neutral effect on survival (P>0.05). PLK1 mRNA 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). CDC25c mRNA expression did not significantly differ between myelofibrosis and controls (P=0.162). Higher CDC25c mRNA was significantly associated with unfavourable prognostic factors: higher white blood cells count (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) and inferior overall survival (HR=2.99; P=0.049). In conclusion, these genes effects survival and seem to be involved in pathogenesis of myelofibrosis. Future studies investigating these genes in hematological malignancies, as well as in reactive disorders, are warranted

Aurora kinase A / Polo-like kinase 1 signaling pathway analysis in patients with myelofibrosis

Aurora kinaza A (AURKA), protein Aurora borealis (BORA), Polo-like kinaza 1 (PLK1) i Cell-division-cycle 25c (CDC25c) kontroliraju stanični ciklus i ulazak stanice u mitozu, a njihova disregulacija opisana je u brojnim malignim bolestima. Cilj rada bio je ispitati do sad nedovoljno istražen izražaj njihovih mRNA u mijeloproliferativnoj bolesti, mijelofibrozi (MF). Iz citoloških punktata koštane srži urađena je PCR mRNA analiza navedenih gena u 43 bolesnika s mijelofibrozom, i to 28 s primarnom (PMF) i 15 sa sekundarnom mijelofibrozom (SMF). U kontrolnim skupinama bilo je 12 ispitanika s agresivnim ne-Hodgkinovim limfom bez infiltracije koštane srži i 6 ispitanika s reaktivnom promjenom koštane srži bez zloćudne bolesti. Optimalne granične vrijednosti izražaja mRNA za diskriminaciju preživljenja odabrane su korištenjem analize ROC krivulje. Nije bilo značajne razlike u izražaju AURKA mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.466). Viša vrijednost izražaja AURKA mRNA značajno je povezana s većim apsolutnim brojem monocita (P=0.024) i kraćim ukupnim preživljenjem (HR=3.77; P=0.012). U bolesnika s PMF i SMF značajno je niži izražaj BORA mRNA u odnosu na kontrolne ispitanike (P=0.009). Viša vrijednost izražaja BORA mRNA značajno je povezana s povoljnim prognostičkim pokazateljima: odsutnošću konstitucijskih simptoma (P=0.049) i cirkulirajućih blasta (P=0.047), ali bez značajne povezanosti s ukupnim preživljenjem (P>0.05). Nije bilo značajne razlike u izražaju PLK1 mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.103). Viša vrijednost izražaja PLK1 mRNA značajno je povezana s većim ukupnim brojem leukocita (P=0.042) i kraćim ukupnim preživljenjem (HR=5.87; P=0.003). Nije bilo značajne razlike u izražaju CDC25c mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.162). Viša vrijednost izražaja CDC25c mRNA značajno je povezana s nepovoljnim prognostičkim pokazateljima: većom jetrom (P=0.022), većim ukupnim brojem leukocita (P=0.017), većim apsolutnim brojem neutrofila (P=0.010), monocita (P=0.050), bazofila (P=0.012) i eozinofila (P=0.013) te kraćim ukupnim preživljenjem (HR=2.99; P=0.049). Izražaj ovih gena ima utjecaj na ukupno preživljenje u mijelofibrozi te istraživanje treba proširiti na druge hematološke zloćudne bolesti i one s reaktivnim i prolaznim promjenama hematopoeze.Aurora kinase A (AURKA), Aurora borealis protein (BORA), Polo-like kinase 1 (PLK1) and Cell-division-cycle 25c (CDC25c) are required for cell cycle control and promotion of mitosis entry. Their dysregulation has been described in a number of malignant diseases. However, their role in pathogenesis of myelofibrosis is less known. We investigated AURKA, BORA, PLK1 and CDC25c mRNA expression in bone marrow aspirates of 43 patients with myelofibrosis (28 primary - PMF, 15 secondary myelofibrosis - SMF) and 18 controls (the first control group of 12 with limited stage of aggressive non Hodgkin lymphoma without bone marrow involvement and the second group of 6 with nonmalignant reactive bone marrow). Optimal cut-off values for dichotomization of expression levels of investigated genes for the purpose of survival analysis were done using the ROC curve analysis with survival status as a classification variable. AURKA mRNA 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 mRNA expression than controls (P=0.009). Higher BORA expression was significantly associated with favourable prognostic factors: absence of constitutional symptoms (P=0.049) and absence of circulatory blasts (P=0.047), but with neutral effect on survival (P>0.05). PLK1 mRNA 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). CDC25c mRNA expression did not significantly differ between myelofibrosis and controls (P=0.162). Higher CDC25c mRNA was significantly associated with unfavourable prognostic factors: higher white blood cells count (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) and inferior overall survival (HR=2.99; P=0.049). In conclusion, these genes effects survival and seem to be involved in pathogenesis of myelofibrosis. Future studies investigating these genes in hematological malignancies, as well as in reactive disorders, are warranted

Aurora kinase A / Polo-like kinase 1 signaling pathway analysis in patients with myelofibrosis

Aurora kinaza A (AURKA), protein Aurora borealis (BORA), Polo-like kinaza 1 (PLK1) i Cell-division-cycle 25c (CDC25c) kontroliraju stanični ciklus i ulazak stanice u mitozu, a njihova disregulacija opisana je u brojnim malignim bolestima. Cilj rada bio je ispitati do sad nedovoljno istražen izražaj njihovih mRNA u mijeloproliferativnoj bolesti, mijelofibrozi (MF). Iz citoloških punktata koštane srži urađena je PCR mRNA analiza navedenih gena u 43 bolesnika s mijelofibrozom, i to 28 s primarnom (PMF) i 15 sa sekundarnom mijelofibrozom (SMF). U kontrolnim skupinama bilo je 12 ispitanika s agresivnim ne-Hodgkinovim limfom bez infiltracije koštane srži i 6 ispitanika s reaktivnom promjenom koštane srži bez zloćudne bolesti. Optimalne granične vrijednosti izražaja mRNA za diskriminaciju preživljenja odabrane su korištenjem analize ROC krivulje. Nije bilo značajne razlike u izražaju AURKA mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.466). Viša vrijednost izražaja AURKA mRNA značajno je povezana s većim apsolutnim brojem monocita (P=0.024) i kraćim ukupnim preživljenjem (HR=3.77; P=0.012). U bolesnika s PMF i SMF značajno je niži izražaj BORA mRNA u odnosu na kontrolne ispitanike (P=0.009). Viša vrijednost izražaja BORA mRNA značajno je povezana s povoljnim prognostičkim pokazateljima: odsutnošću konstitucijskih simptoma (P=0.049) i cirkulirajućih blasta (P=0.047), ali bez značajne povezanosti s ukupnim preživljenjem (P>0.05). Nije bilo značajne razlike u izražaju PLK1 mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.103). Viša vrijednost izražaja PLK1 mRNA značajno je povezana s većim ukupnim brojem leukocita (P=0.042) i kraćim ukupnim preživljenjem (HR=5.87; P=0.003). Nije bilo značajne razlike u izražaju CDC25c mRNA između ispitanika s MF i kontrolnih ispitanika (P=0.162). Viša vrijednost izražaja CDC25c mRNA značajno je povezana s nepovoljnim prognostičkim pokazateljima: većom jetrom (P=0.022), većim ukupnim brojem leukocita (P=0.017), većim apsolutnim brojem neutrofila (P=0.010), monocita (P=0.050), bazofila (P=0.012) i eozinofila (P=0.013) te kraćim ukupnim preživljenjem (HR=2.99; P=0.049). Izražaj ovih gena ima utjecaj na ukupno preživljenje u mijelofibrozi te istraživanje treba proširiti na druge hematološke zloćudne bolesti i one s reaktivnim i prolaznim promjenama hematopoeze.Aurora kinase A (AURKA), Aurora borealis protein (BORA), Polo-like kinase 1 (PLK1) and Cell-division-cycle 25c (CDC25c) are required for cell cycle control and promotion of mitosis entry. Their dysregulation has been described in a number of malignant diseases. However, their role in pathogenesis of myelofibrosis is less known. We investigated AURKA, BORA, PLK1 and CDC25c mRNA expression in bone marrow aspirates of 43 patients with myelofibrosis (28 primary - PMF, 15 secondary myelofibrosis - SMF) and 18 controls (the first control group of 12 with limited stage of aggressive non Hodgkin lymphoma without bone marrow involvement and the second group of 6 with nonmalignant reactive bone marrow). Optimal cut-off values for dichotomization of expression levels of investigated genes for the purpose of survival analysis were done using the ROC curve analysis with survival status as a classification variable. AURKA mRNA 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 mRNA expression than controls (P=0.009). Higher BORA expression was significantly associated with favourable prognostic factors: absence of constitutional symptoms (P=0.049) and absence of circulatory blasts (P=0.047), but with neutral effect on survival (P>0.05). PLK1 mRNA 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). CDC25c mRNA expression did not significantly differ between myelofibrosis and controls (P=0.162). Higher CDC25c mRNA was significantly associated with unfavourable prognostic factors: higher white blood cells count (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) and inferior overall survival (HR=2.99; P=0.049). In conclusion, these genes effects survival and seem to be involved in pathogenesis of myelofibrosis. Future studies investigating these genes in hematological malignancies, as well as in reactive disorders, are warranted

Higher estimated plasma volume status is associated with increased thrombotic risk and impaired survival in patients with primary myelofibrosis

IntroductionBlood 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. Materials and methodsWe 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. ResultsMedian 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 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. ConclusionsMyelofibrosis 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

MPN-541 Estimated Plasma Volume Status in Patients With Primary Myelofibrosis and Associated Thrombotic and Mortality Risks

Context: 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. Objective: To estimate clinical and prognostic associations of ePVS in patients with myelofibrosis. Design: Retrospective cohort study. Setting: 6 hematology centers. Patients: 238 myelofibrosis patients, 168 with PMF, 34 with post-PV SMF and 36 with post-ET SMF. Interventions: ePVS was calculated using the Strauss derived Duarte formula: (100-hematocrit (%)/hemoglobin (g/dL) and expressed as dl/g. Main outcome measures: Overall survival (OS) and time to thrombosis (TTT). Results: 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 (P5.6 dl/g) was associated with shorter overall-survival (OS) in PMF (HR=2.8, P7 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. Conclusions: 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

Evaluation of Absolute Neutrophil, Lymphocyte and Platelet Count and Their Ratios as Predictors of Thrombotic Risk in Patients with Prefibrotic and Overt Myelofibrosis

Aim: To investigate the prognostic contribution of absolute neutrophil (ANC), lymphocyte (ALC), platelet count and their ratios, neutrophil–lymphocyte ratio (NLR) and platelet–lymphocyte ratio (PLR), to thrombotic risk in patients with prefibrotic and overt fibrotic myelofibrosis (MF). Methods: We retrospectively analyzed a cohort of 256 patients with prefibrotic (85 patients) and overt fibrotic MF (171 patients) treated in six Croatian hematological centers. Results: Prefibrotic compared to overt fibrotic MF patients presented with significantly higher ALC, platelet count and PLR, and experienced longer time to thrombosis (TTT). Among prefibrotic patients, ANC > 8.33 × 109/L (HR 13.08, p = 0.036), ALC > 2.58 × 109/L (HR 20.63, p = 0.049) and platelet count > 752 × 109/L (HR 10.5, p = 0.043) remained independently associated with shorter TTT. Among overt fibrotic patients, ANC > 8.8 × 109/L (HR 4.49, p = 0.004), ALC ≤ 1.43 × 109/L (HR 4.15, p = 0.003), platelet count ≤ 385 × 109/L (HR 4.68, p = 0.004) and chronic kidney disease (HR 9.07, p < 0.001) remained independently associated with shorter TTT. Conclusions: Prognostic properties of ANC, ALC and platelet count are mutually independent and exceed those of NLR and PLR regarding thrombotic risk stratification. ALC and platelet count associate in opposite directions with thrombotic risk in prefibrotic and overt fibrotic MF patients

Reduced renal function strongly affects survival and thrombosis in patients with myelofibrosis

We retrospectively investigated a cohort of 176 myelofibrosis patients (128 primary-PMF; 48 secondary-SMF) from five hematology centers. The presence of chronic kidney disease (CKD) was determined in addition to other clinical characteristics. CKD was present in 26.1% of MF patients and was significantly associated with older age (P 0.05 for all analyses). The presence of CKD was significantly associated with shorter time to arterial (HR = 3.49; P = 0.041) and venous thrombosis (HR = 7.08; P = 0.030) as well as with shorter overall survival (HR 2.08; P = 0.009). In multivariate analyses, CKD (HR = 1.8; P = 0.014) was associated with shorter survival independently of the DIPSS (HR = 2.7; P < 0.001); its effect being more pronounced in lower (HR = 3.56; P = 0.036) than higher DIPSS categories (HR = 2.07; P = 0.023). MF patients with CKD should be candidates for active management aimed at the improvement of renal function. Prospective studies defining the optimal therapeutic approach are highly needed

Glycated hemoglobin (HbA1c) and thrombotic risk in polycythemia vera and essential thrombocythemia

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